Pharmaceutical composition of salbutamol and pharmaceutical green propellant

Abstract

Disclosed is a pharmaceutical composition for inhalation comprising salbutamol, or an enantiomer, or a salt, or ester thereof, and a pharmaceutically acceptable green propellant. In particular, disclosed is a pharmaceutical composition for inhalation comprising salbutamol, or an enantiomer, or a salt, or ester thereof, and a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze (E). Also disclosed are methods of making such compositions.

Description

[0001] Priority Details

[0002] This application claims the benefit of Indian Provisional Application No. 202221045748 and Indian Provisional Application No. 202221045818, filed on August 10, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to a pharmaceutical composition for inhalation, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant. In particular, disclosed is a pharmaceutical composition for inhalation, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E). Also disclosed are methods for preparing such a composition and methods for using such a composition to prevent or treat respiratory disorders. Background Art

[0004] Hydrofluoroalkanes (HFAs) have been used as propellants in pressurized metered-dose inhalers (pMDIs) for many years. They replaced the ozone-depleting chlorofluorocarbons (CFCs). HFAs were introduced as alternative propellants in inhalers in 1987. Two HFAs, specifically 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 atomize drugs from pMDIs. These HFAs provide many of the same benefits as CFCs for many inhaler device applications - high propellant performance and non-toxicity to humans - and also have the advantage of not interacting with the ozone layer. Thus, drug devices containing HFAs have been widely distributed globally. However, they do have significant drawbacks. They have a relatively high global warming potential (GWP), which means they trap relatively high levels of solar heat in the atmosphere, doing so contributing significantly to climate change (Report on the UK's progress in reducing fluorinated gas emissions, 2017 - 19, 5th session, House of Commons, published on April 25, 2018). GWP is the amount of heat absorbed by any greenhouse gas in the atmosphere, expressed as a multiple of the amount of heat absorbed by the same mass of carbon dioxide (CO 2 )). The GWP of CO 2 is 1. For other gases, it depends on the gas and the time frame. The higher the number, the higher the GWP. The GWP of 1,1,1,2-tetrafluoroethane (HFC-134a), commonly used in pMDIs, is 1430, which means it absorbs 1430 times the amount of heat of the same mass of CO 2 .

[0005] The inhaler market is expected to grow at a compound annual growth rate (CAGR) of 7.1% to reach over $2 billion, and accordingly, the number of inhalers to be dispensed will also increase. Therefore, the inability to find a more sustainable alternative propellant now could mean that patients may not have access to important and effective inhaled drug products in the future. Consumers and businesses are increasingly concerned about reducing their impact on the environment. More and more consumers and businesses are taking steps to reduce their environmental footprint. More and more businesses are looking to engage and collaborate with similarly "green" suppliers.

[0006] The pharmaceutical industry has been exploring alternatives to the standard propellants used in inhaled drug delivery devices and other medical devices. Two potential "greener" candidates currently under consideration are: 1,1-difluoroethane (HFA-152a) and 1,3,3,3-tetrafluoropropene (HFO-1234ze(E)). These next-generation propellants offer several key benefits for inhaled drug developers. They are more environmentally friendly than traditional HFAs and exhibit a lower GWP. For example, HFA-152a has a GWP of 124 compared to 1430 for the traditional inhaler propellant 1,1,1,2-tetrafluoroethane (HFC-134a). At the same time, HFO-1234ze(E) has a GWP of less than 1, even lower than that of CO 2 2. These GWP figures mean that when in the atmosphere, both HFA-152a and HFO-1234ze(E) trap less heat from the sun, resulting in a less significant global heating effect. In addition, they have a much shorter atmospheric lifetime (AL) compared to existing propellants. For example, HFA-152a has an AL of 1.4 years compared to 14 years for the inhaler propellants currently in use. 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%20changing%20climate.pdf).

[0007] Although they offer important and exciting environmental benefits, the new generation of propellants do have certain drawbacks that need to be considered before being adopted by the pharmaceutical industry. These drawbacks include: (1) The use of these new propellants is still in its infancy not only in the pharmaceutical field but also in other areas of the economy, and it is too early to say whether they are a direct and effective substitute for traditional propellants. (2) Like other gases, both HFA-152a and HFO-1234ze(E) have their own unique properties, which means that further work must be done to adjust the pMDI device design in order to produce effective finished products with sufficient shelf life. In addition, several other factors need to be determined when considering new propellants in pharmaceutical formulations, such as the toxicology of the propellants, the interaction of the new propellants with the drug and the device, the interaction of the new propellants with the manufacturing equipment, etc. Even after all this, pharmaceutical companies must overcome regulatory hurdles and make the product accessible to patients on the market at an affordable price.

[0008] Salbutamol or albuterol is approved as a pMDI in the United States under the trade names VENTOLIN HFA, PROAIR HFA, and PROVENTIL HFA. The active ingredient of Ventolin HFA is salbutamol sulfate (USP, the racemic form of salbutamol), and what is provided as VENTOLIN HFA is a blue plastic inhaler with a blue cap, containing a pressurized metered-dose aerosol can equipped with a counter. Each can contains a microcrystalline suspension of salbutamol sulfate in the propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients. PROVENTIL HFA Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline suspension of salbutamol sulfate in the propellant HFA-134a (1,1,1,2-tetrafluoroethane), ethanol, and oleic acid. PROAIR HFA Inhalation Aerosol is a pressurized metered-dose aerosol unit with a dose counter. PROAIR HFA is for oral inhalation only. It contains a microcrystalline suspension of salbutamol sulfate in the propellant HFA-134a (1,1,1,2-tetrafluoroethane) and ethanol. Levosalbutamol or levalbuterol ((R)-enantiomer of the drug substance racemic salbutamol) is approved as a pMDI in the United States under the trade name XOPENEX HFA, which is a suspension of micronized levalbuterol tartrate, the propellant HFA-134a (1,1,1,2-tetrafluoroethane), anhydrous ethanol USP, and oleic acid NF. After being primed with 4 actuations, each actuation of the inhaler delivers 67.8 micrograms (mcg) of levalbuterol tartrate (equivalent to 51.6 mcg of levalbuterol free base) from the valve and 59 mcg of levalbuterol tartrate (equivalent to 45 mcg of levalbuterol free base) from the actuator nozzle. Each 15 g can provides 200 actuations (or inhalations). Levosalbutamol is also approved as an inhalation solution, supplied in unit-dose vials and does not require dilution before administration by nebulization. Each 3 mL unit-dose vial contains 0.63 mg of levalbuterol (0.73 mg of levalbuterol hydrochloride) or 1.25 mg of levalbuterol (1.44 mg of levalbuterol hydrochloride), sodium chloride for tonicity adjustment, and sulfuric acid for pH adjustment to 4.0 (3.3 to 4.5).

[0009] U.S. Patent 9,114,164, U.S. Patent 9,517,216, U.S. Patent 10,959,965, U.S. Patent Application 2021 / 0244688A1, and U.S. Patent Application 2021 / 0244688A1 disclose aerosol compositions of salbutamol sulfate with HFA-152a.

[0010] However, there is a need for such pMDI aerosol formulations that have a reduced GWP compared to HFA-134a and HFA-227ea, that have acceptable flammability and toxicity properties, and that form a stable suspension or solution with salbutamol or levalbuterol, or their salts or esters. Summary of the Invention

[0012] In a first aspect of the present invention, there is provided a pharmaceutical composition for inhalation, which comprises salbutamol or its enantiomer, or a salt, or an ester and a pharmaceutically acceptable green propellant.

[0013] In another aspect, there is provided a pharmaceutical composition for inhalation, which comprises salbutamol or its enantiomer, or a salt, or an ester and a pharmaceutically acceptable green propellant HFA-152a. In one embodiment, the HFA-152a is present in the composition at a concentration of at least 30% or 40% or 50% or 60% or 70% or 80% or 90% or 99%. In another embodiment, the HFA-152a is present in the composition at a concentration of at least 90%. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of water, or based on the total weight of the pharmaceutical composition, the composition contains less than 400 ppm of water, or based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of water. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of oxygen, or wherein based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of oxygen, or based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of oxygen. In another embodiment, the propellant HFA-152a is greater than 90% or 95% or 99% or 99.5% or 99.99% pure. In another embodiment, the propellant HFA-152a does not have any substantial impurities or contains no impurities, or the propellant HFA-152a contains less than 0.5 ppm to 10 ppm of unsaturated impurities or less than 0.25 ppm of unsaturated impurities. The composition further comprises a pharmaceutically acceptable excipient.

[0014] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant HFO-1234ze(E). The HFO-1234ze(E) is present in the composition at the following concentrations: at least 30% or 40% or 50% or 60% or 70% or 80% or 90% or 99%. More preferably, the HFO-1234ze(E) is present in the composition at a concentration of at least 90%. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of water, or based on the total weight of the pharmaceutical composition, the composition contains less than 400 ppm of water, or based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of water. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of oxygen, or based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of oxygen, or based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of oxygen. In another embodiment, the propellant HFO-1234ze(E) is greater than 90% or 95% or 99% or 99.5% or 99.99% pure. Preferably, the propellant HFO-1234ze(E) does not have any substantial impurities or contains no impurities. More preferably, the propellant HFO-1234ze(E) contains less than 0.5 ppm to 10 ppm of unsaturated impurities or less than 0.25 ppm of unsaturated impurities, or the propellant HFO-1234ze(E) contains less than 10 ppm of HFO-1234ze(Z), or the propellant HFO-1234ze(E) contains less than 5 ppm of HFO-1234ze(Z). The composition further comprises a pharmaceutically acceptable excipient.

[0015] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, and the propellant is a combination of HFO-1234ze(E) and HFA-152a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and a surfactant selected from oleic acid, polyvinylpyrrolidone of different K grades, lecithin, Tween 20, sorbitan trioleate, sorbitan monooleate, Tween 80, polyethylene glycol with a level of 200-1500, and combinations thereof. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and oleic acid. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol and oleic acid.

[0016] Also disclosed herein is a method for preparing such a composition. In one embodiment, the sedimentation rate of the active agent in the propellant medium depends on the preparation method of the composition. In another embodiment, the composition of the present invention is prepared by (1) an ultrasonic treatment method, or (2) a single-stage filling method, or (3) a two-stage filling method.

[0017] The composition of the present invention is suitable for oral or nasal inhalation routes. The administration or delivery of the composition can be accomplished using a pressurized metered-dose inhaler (pMDI), or a breath-actuated inhaler (BAI), or a nebulizer (Neb). The composition of the present invention can be used to prevent or treat respiratory disorders using such a composition. Description of the Drawings

[0018] Figure 1 : This figure shows a visual image of vials with suspension compositions prepared according to Examples 14A, 14B, 14C, and 14D. Detailed Description

[0019] Unless otherwise specifically defined, technical terms as used herein have their normal meanings as understood in the art. For clarity, the following terms are specifically defined.

[0020] As used herein, the term "active agent" includes agents such as drugs, compounds, compositions, or other substances that can be used or administered to a human or animal for any purpose, including therapeutic agents, pharmaceutical substances, pharmacological agents, diagnostic agents, cosmetic agents, prophylactic agents, and immunomodulators. The active agent can be used interchangeably with the terms drug, pharmaceutical API, medicine, drug substance, or therapeutic agent.

[0021] As used herein, "mass median aerodynamic diameter" or "MMAD" refers to the aerodynamic diameter of an aerosol below which 50% of the mass of the aerosol is contained in particles with an aerodynamic diameter less than the MMAD, where the MMAD is calculated according to the monograph 601 of the United States Pharmacopeia ("USP").

[0022] As used herein, "ultrafine particles" refers to particles having an MMAD of less than 2 μm or preferably less than 1 μm.

[0023] As used herein, "ultrafine aerosol formulation or composition, or ultrafine suspension" refers to a composition in which greater than 50% or 60% or 70% or 80% or 90% or 95% of the particles have an MMAD of less than 2 μm or preferably less than 1 μm.

[0024] A "therapeutically effective amount" is the amount of a compound that achieves a therapeutic effect by suppressing a disease or disorder in a patient or by prophylactically suppressing or preventing the onset of a disease or disorder, particularly a respiratory disorder. A therapeutically effective amount can be an amount that alleviates to some extent one or more symptoms of the patient's disease or disorder; an amount that partially or completely restores to normal one or more physiological or biochemical parameters associated with or caused by the disease or disorder; and / or an amount that reduces the likelihood of the onset of the disease or disorder.

[0025] The term "stable" or "chemically stable" refers to a composition in which the various degradation products of the active agent remain below the limits specified by regulatory requirements (e.g., 1% of the total chromatographic peak area according to ICH guideline Q3B(R2)) during the shelf life of the human product and there is an acceptable mass balance between the active agent assay value and the total degradation products (e.g., as defined in ICH guideline Q1E).

[0026] The term "substantially" means greater than 90% or 95% or 99% or 99.99%. For example, the propellant being substantially free of any impurities means that the impurities in the propellant or impurities associated with the propellant are less than 10%, or less than 5%, or less than 1%, or are absent from the propellant.

[0027] The term "% w / w" refers to the weight of a specific active agent or excipient based on the weight of the composition.

[0028] The active agent present in the present invention is salbutamol or levalbuterol or their salts or esters, and both are short-acting bronchodilators used for the treatment and control of several respiratory-related conditions, particularly asthma and chronic obstructive pulmonary disease (COPD). The drug is conveniently delivered using a pMDI or a breath-actuated MDI (BAI). In particular, the present invention relates to salbutamol sulfate, levalbuterol hydrochloride, or levalbuterol tartrate, or combinations thereof. The terms "salbutamol" and "albuterol" are used interchangeably throughout the specification. Similarly, the terms "levosalbutamol" and "levalbuterol" are used interchangeably throughout the specification.

[0029] In one embodiment, the composition of the present invention comprises from about 0.05% to about 0.8% by weight of salbutamol, or its salt, or ester. In another embodiment, the composition of the present invention comprises from about 0.05% to about 0.8% by weight of levalbuterol, or its salt, or ester. In another embodiment, the composition of the present invention comprises about 0.1% or 0.2% or 0.3% or 0.4% or 0.5% or 0.6% or 0.7% or about 0.8% by weight of salbutamol, or its salt, or ester. In another embodiment, the composition of the present invention comprises about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%, or 0.6%, or 0.7%, or about 0.8% by weight of levalbuterol, or its salt, or ester. In a preferred embodiment, the active agent is salbutamol sulfate. In another preferred embodiment, the active agent is levalbuterol hydrochloride. In another preferred embodiment, the active agent is levalbuterol tartrate.

[0030] There is a need for pharmaceutical compositions containing salbutamol, or levalbuterol, or their salts or esters, which can be delivered using a pMDI or BAI and using a propellant having a reduced GWP compared to HFA-134a and HFA-227ea. There is also a need for pharmaceutical compositions containing salbutamol that exhibit improved stability during shelf life. The inventors of the present invention have discovered a stable pharmaceutical composition for inhalation that can be delivered not only by pMDI but also using BAI or a nebulizer device, wherein the composition is prepared using a propellant having a low GWP such as HFA-152a and / or HFO-1234ze(E).

[0031] HFA-152a( 152a) is a new and sustainable medical propellant that has been developed by Koura for many years for use in pMDIs to treat respiratory conditions such as asthma and COPD. The following are some specific physicochemical properties of HFA-152a. In addition to HFA-152a, hydrofluoroolefins (HFOs) are a unique series of products that offer performance comparable to the most widely used stationary and mobile refrigerants, blowing agents, and aerosol propellants today. HFO-1234ze(E) (Solstice) is trans-1,3,3,3-tetrafluoroprop-1-ene. The suffix (E) indicates that it is an isomer. The other isomer (suffix (Z)) is cis-1,3,3,3-tetrafluoroprop-1-ene. The physical properties of the (E) and (Z) isomers are different: both are ultra-low GWP molecules with a GWP < 1.

[0032] In a first embodiment of the present invention, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant. The composition of the present invention is suitable for oral or nasal inhalation routes. Administration or delivery of the composition can be accomplished using a pMDI, or BAI, or a nebulizer (Neb).

[0033] A pressurized metered-dose inhaler is an inhaler that delivers an aerosolized dose of a pharmaceutical composition using a pressurized liquefied propellant. A pressurized metered-dose inhaler typically comprises a canister (or bottle) that includes a liquid pharmaceutical composition, a metering valve, a actuator, and a mouthpiece. To improve the stability of the composition, various canister specifications can also be used, such as 19 ml coated canisters, 14 ml regular canisters, 14 ml coated canisters. Similarly, various capacity valves such as 25 mcl, 50 mcl can also be used to minimize the residue of the active agent in the canister. In addition, the actuator can be equipped with a dose counter that is currently available or known. To improve the performance of the product during shelf life, various valves with gaskets such as EPDM, nitrile, COCE, Buna, etc. can be used. In the case of a breath-actuated inhaler, a similar type of canister or valve can be used. Pressurized metered-dose inhalers are well known to those of ordinary skill in the art, and many such devices are commercially available, representative devices including the AeroBid inhaler system (Forest Pharmaceuticals), Atrovent inhaled aerosol (Boehringer Ingelheim), FloventR TM (GlaxoSmithKline), Maxair inhaler (3M), ProventilR TM inhaler (Schering) and SereventR TMInhalation aerosol (GlaxoSmithKline). In addition, various breath-actuated inhalers available on the market are Synchrobreathe TM , Redihaler TM , Easibreathe TM , and other available breath-actuated inhalers. Moreover, the compositions (solutions or suspensions) of the present invention can also be delivered using currently available nebulizers, such as Philips I-Neb TM (Philips), Pari LC Sprint (Pari GmbH), Lung Delivery System (Aradigm Corp.) and Pari LC Plus reusable nebulizer (Pari GmbH).

[0034] When delivering the composition using a pMDI or BAI, in some embodiments, 120 mcg of salbutamol sulfate is delivered from the valve and 108 mcg is delivered from the mouthpiece per actuation, which is equivalent to 90 mcg of salbutamol base. In another preferred embodiment, 67.8 mcg of levalbuterol tartrate (equivalent to 51.6 mcg of levalbuterol free base) is delivered from the valve and 59 mcg of levalbuterol tartrate (equivalent to 45 mcg of levalbuterol free base) is delivered from the actuator mouthpiece per actuation.

[0035] In a further embodiment, the pharmaceutical composition is prepared in the form of a suspension or a solution. The active agent present in the composition is micronized (MMAD is 3 to 5 μm) or ultrafine (MMAD is less than 2 or 1 μm). More specifically, the suspension composition contains micronized active agent, and the solution composition contains ultrafine active agent. In the ultrafine composition, the particle size of the active agent, i.e., MMAD, is less than 1 μm or 2 μm. In addition, for the suspension composition of the present invention, the active agent particles have a particle size distribution with a Dv50 (volume median diameter) value of about 0.2 μm to about 5 μm. More generally, the particles of the active agent have a Dv50 value of about 0.7 μm to about 3.0 μm. For example, the particles of the active agent (salbutamol or its enantiomer, or salt, or ester) can have a particle size distribution with a Dv50 value of 0.9 μm to 1.7 μm, or 1.7 μm to 2.7 μm. The particles of salbutamol or its enantiomer, or salt, or ester generally have a Dv50 value of about 1.1 μm to about 2.6 μm.

[0036] The pharmaceutical composition further comprises a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is selected from, but not limited to, solvents, surfactants, solubilizers, lubricants, buffers, pH regulators, or combinations thereof. Solvents or co-solvents, carrier solvents, and adjuvants are collectively referred to as excipients, which are used to dissolve surfactants or drugs in the propellant and / or inhibit the deposition of drug particles on the surface of the metered-dose inhaler (the pharmaceutical composition contacts the surface when transferred from the container storing it to the nozzle outlet). Based on the weight of the composition, the amount of the solvent can be 0.5% to 25.0%, or 1% to 10%, or 15%. Generally, the solvent can be added to the composition in an appropriate quantity (q.s.) according to the concentration of other components and the total volume of the composition. Examples of the solvent are, but not limited to, ethanol, water, propanol, isopropanol, or combinations thereof. In one embodiment, ethanol is the preferred solvent and is present at a concentration of about 1%, or 5%, or 10%, or 15% based on the weight of the composition.

[0037] In an alternative embodiment, the composition comprises water as the preferred solvent. In another alternative embodiment, the composition is water-free and formulated as a non-aqueous composition, where ethanol is the preferred solvent. Preferably, the water content is less than 1000 ppm, or 400 ppm, or 5 ppm, or 1 ppm.

[0038] The surfactant or solubilizer helps to dissolve or stabilize salbutamol or its enantiomers, or salts, or esters. Preferred examples of the surfactant are, but not limited to, polyvinylpyrrolidone, polyethylene glycol, oleic acid, lecithin, polysorbate, or combinations thereof. The concentration of the surfactant is 0.001% to 2% of the weight of the composition. The composition may comprise a lubricant selected from, but not limited to, glycerol, dimethicone, silica, and magnesium stearate, or combinations thereof. The amount of the lubricant present is 0.001% to 2% of the weight of the composition. The preferred concentration is 0.1% of the weight of the composition. Those skilled in the art can use pH regulators, such as any strong acid (such as hydrochloric acid), or strong base (such as sodium hydroxide), or combinations thereof. In addition, those skilled in the art can also add buffers, such as weak acids, weak bases, strong acid + weak base, or weak acid + strong base. For example, citric acid, acetic acid, malic acid, tartaric acid, sodium citrate, sodium phosphate, potassium phosphate, glycine, and other conventional buffers known to those skilled in the art.

[0039] In a preferred embodiment, the active agent in the pharmaceutical composition is salbutamol base, or salbutamol sulfate, or levalbuterol base, or levalbuterol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride. In another embodiment, the salbutamol sulfate is present at the following concentrations: 0.05% w / w to 1% w / w of the composition, or preferably 0.1% w / w to 0.5% w / w, or more preferably 0.2% w / w to 0.4% w / w. In a preferred embodiment, the salbutamol sulfate is present at about 0.16% w / w or about 0.21% w / w of the composition. Similarly, levalbuterol base, or levalbuterol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride are present at the following concentrations: 0.05% w / w to 1% w / w of the composition, or preferably 0.1% w / w to 0.5% w / w, or more preferably 0.2% w / w to 0.4% w / w. In a preferred embodiment, the levalbuterol, or levalbuterol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride is present in the composition at a concentration of about 0.16% w / w or about 0.21% w / w. Alternatively, the salbutamol sulfate is present in the composition at the following concentrations: 50 mcg to 400 mcg, or preferably 100 mcg to 200 mcg, or more preferably about 100 mcg or 200 mcg. Alternatively, the salbutamol sulfate is present at the following concentrations: 50 mcg, or 60 mcg, or 70 mcg, or 80 mcg, or 90 mcg, or 100 mcg, or 120 mcg, or 140 mcg, or 160 mcg, or 180 mcg, or 200 mcg. Alternatively, levalbuterol base, or levalbuterol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride are present in the composition at the following concentrations: 50 mcg to 400 mcg, or preferably 100 mcg to 200 mcg, or more preferably about 100 mcg or 200 mcg. Alternatively, levalbuterol base, or levalbuterol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride are present at the following concentrations: 50 mcg, or 60 mcg, or 70 mcg, or 80 mcg, or 90 mcg, or 100 mcg, or 120 mcg, or 140 mcg, or 160 mcg, or 180 mcg, or 200 mcg.

[0040] In another embodiment, when the composition is administered using a pMDI or BAI, the salbutamol sulfate delivered from the valve of the metered-dose inhaler is present at the following concentrations: 50 mcg to 400 mcg, or preferably 100 mcg to 200 mcg, or more preferably about 120 mcg. Similarly, in another embodiment, the levalbuterol base, or levalbuterol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride delivered from the valve of the metered-dose inhaler is present at the following concentrations: 50 mcg to 400 mcg, or preferably 100 mcg to 200 mcg, or more preferably about 67.8 mcg. In another embodiment, the composition is in the form of a suspension and wherein the salbutamol, or levalbuterol base, or its levalbuterol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride is in micronized form. Alternatively, the composition is in the form of an ultrafine composition, wherein more than 50% or 60% or 70% or 80% or 90% or 95% of the particles of salbutamol or its enantiomer, or salt, or ester have an aerodynamic diameter of less than 2 μm or less than 1 μm. The composition in the form of an ultrafine suspension, wherein more than 50% or 60% or 70% or 80% or 90% or 95% of the particles of salbutamol or its enantiomer, or salt, or ester have an aerodynamic diameter of less than 2 μm. When the composition has an ultrafine active agent, then the composition is called a solution. In addition, in a solution composition, the active agent is dissolved in a propellant or other excipient.

[0041] The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable green propellant selected from propellants having a global warming potential value of less than 250, more preferably less than 200, still more preferably less than 150, or less than 100, or less than 50, or less than 20, or less than 10, or less than 5. In another embodiment, the pharmaceutically acceptable green propellant is selected from HFA-152a, or HFO-1234ze(E), or a combination thereof.

[0042] In one embodiment, the pharmaceutically acceptable green propellant is HFA-152a. The green propellant HFA-152a is present in the composition at the following concentrations: at least 30% or 40% or 50% or 60% or 70% or 80% or 90% or 99%. In one embodiment, the pharmaceutically acceptable green propellant HFA-152a is present in the composition at a concentration of at least 90%. The green propellant HFA-152a is greater than 90% or 95% or 99% or 99.5% or 99.99% pure. In another embodiment, the propellant HFA-152a does not have any substantial impurities or contains no impurities. Preferably, the propellant HFA-152a contains less than 0.5 ppm to 10 ppm of unsaturated impurities or less than 0.25 ppm of unsaturated impurities.

[0043] In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm or less than 400 ppm of water. Preferably, based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of water. More preferably, based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of water. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of oxygen. Preferably, based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of oxygen. More preferably, based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of oxygen.

[0044] In another embodiment, when administered using the metered dose inhaler, or breath actuated metered dose inhaler, or nebulizer, the fine particle fraction of the salbutamol or its enantiomer, or salt, or ester produced by the composition is at least 40.0% by weight of the emitted dose of the salbutamol or its enantiomer, or salt, or ester, even after the pharmaceutical composition has been stored at 50 °C and 75% relative humidity for 30, or 60, or 90, or 180 days. In another embodiment, when administered using the metered dose inhaler, or breath actuated metered dose inhaler, or nebulizer, the fine particle fraction of the salbutamol or its enantiomer, or salt, or ester produced by the composition is at least 42% by weight of the emitted dose of the salbutamol or its enantiomer, or salt, or ester, even after the pharmaceutical composition has been stored at 50 °C and 75% relative humidity for 30, or 60, or 90, or 180 days, as compared to a composition comprising salbutamol or its enantiomer, or salt, or ester and propellant HFA134a or HFA227ea.

[0045] In another embodiment, when administered using a metered dose inhaler, or a breath actuated metered dose inhaler, or a nebulizer, the composition produces fine particle mass of salbutamol or its enantiomer, or salt, or ester with less variability during shelf life, having a relative standard deviation of less than 6% or less than 4%. In another embodiment, when administered using a metered dose inhaler, or a breath actuated metered dose inhaler, or a nebulizer, the composition produces fine particle mass of salbutamol or its enantiomer, or salt, or ester with less variability during shelf life compared to a composition comprising salbutamol or its enantiomer, or salt, or ester and a propellant HFA134a or HFA227ea. The relative standard deviation (variability) of a composition comprising salbutamol or its enantiomer, or salt, or ester and a propellant HFA134a or HFA227ea during shelf life is greater than 7% or greater than 7.5%.

[0046] In one embodiment, there is disclosed a pharmaceutical composition for inhalation comprising salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant HFA-152a. In another embodiment, the HFA-152a is present in the composition at a concentration of at least 30% or 40% or 50% or 60% or 70% or 80% or 90% or 99%. In another embodiment, the HFA-152a is present in the composition at a concentration of at least 90%. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm or less than 400 ppm of water, or based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of water, or based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of water. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of oxygen, or wherein based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of oxygen, or based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of oxygen. In another embodiment, the propellant HFA-152a is greater than 90% or 95% or 99% or 99.5% or 99.99% pure. In another embodiment, the propellant HFA-152a does not have any substantial impurities or contains no impurities, or the propellant HFA-152a contains less than 0.5 ppm to 10 ppm of unsaturated impurities or less than 0.25 ppm of unsaturated impurities.

[0047] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant HFA-152a, wherein when administered using a metered-dose inhaler, the fine particle fraction of the salbutamol or its enantiomer, or salt, or ester produced by the composition is at least 40.0% by weight of the delivered dose of the salbutamol or its enantiomer, or salt, or ester, even after the pharmaceutical composition has been stored at 50 °C and 75% relative humidity for 30, or 60, or 90, or 180 days.

[0048] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant HFA-152a, wherein when administered using a metered-dose inhaler, the fine particle fraction of the salbutamol or its enantiomer, or salt, or ester produced by the composition is at least 42% by weight of the delivered dose of the salbutamol or its enantiomer, or salt, or ester, even after the pharmaceutical composition has been stored at 50 °C and 75% relative humidity for 30, or 60, or 90, or 180 days, as compared to a composition comprising salbutamol or its enantiomer, or salt, or ester and propellant HFA134a or HFA227ea.

[0049] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant HFA-152a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant HFA-152a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant HFA-152a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant HFA-152a as the sole propellant. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant HFA-152a as the sole propellant. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant HFA-152a as the sole propellant.

[0050] In alternative embodiments, there are disclosed pharmaceutical compositions for inhalation comprising salbutamol sulfate and a pharmaceutically acceptable green propellant, said propellant being a combination of HFA-152a and HFA134a. In another embodiment, there is disclosed a pharmaceutical composition for inhalation comprising levalbuterol tartrate and a pharmaceutically acceptable green propellant, said propellant being a combination of HFA-152a and HFA134a. In another embodiment, there is disclosed a pharmaceutical composition for inhalation comprising levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, said propellant being a combination of HFA-152a and HFA134a.

[0051] In another embodiment, there are disclosed pharmaceutical compositions for inhalation comprising salbutamol sulfate and a pharmaceutically acceptable green propellant, said propellant being a combination of HFA-152a and HFA227ea. In another embodiment, there is disclosed a pharmaceutical composition for inhalation comprising levalbuterol tartrate and a pharmaceutically acceptable green propellant, said propellant being a combination of HFA-152a and HFA227ea. In another embodiment, there is disclosed a pharmaceutical composition for inhalation comprising levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, said propellant being a combination of HFA-152a and HFA227ea.

[0052] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 20% to 90% by weight of the composition, and HFA134a is present at a concentration of 20% to 90% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 70% by weight of the composition, and HFA134a is present at a concentration of 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 30% by weight of the composition, and HFA134a is present at a concentration of 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 20% to 90% by weight of the composition, and HFA134a is present at a concentration of 20% to 90% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 70% by weight of the composition, and HFA134a is present at a concentration of 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 30% by weight of the composition, and HFA134a is present at a concentration of 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 20% to 90% by weight of the composition, and HFA134a is present at a concentration of 20% to 90% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 70% by weight of the composition, and HFA134a is present at a concentration of 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFA-152a and HFA134a, and wherein HFA-152a is present at a concentration of 30% by weight of the composition, and HFA134a is present at a concentration of 70% by weight of the composition.

[0053] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant HFO-1234ze(E). The HFO-1234ze(E) is present in the composition at the following concentrations: at least 30% or 40% or 50% or 60% or 70% or 80% or 90% or 99%. More preferably, the HFO-1234ze(E) is present in the composition at a concentration of at least 90%. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm or 400 ppm of water, or based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of water, or based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of water. In another embodiment, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of oxygen, or based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of oxygen, or based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of oxygen. In another embodiment, the propellant HFO-1234ze(E) is greater than 90% or 95% or 99% or 99.5% or 99.99% pure. Preferably, the propellant HFO-1234ze(E) does not have any substantial impurities or contains no impurities. More preferably, the propellant HFO-1234ze(E) contains less than 0.5 ppm to 10 ppm of unsaturated impurities or less than 0.25 ppm of unsaturated impurities, or the propellant HFO-1234ze(E) contains less than 10 ppm of HFO-1234ze(Z), or the propellant HFO-1234ze(E) contains less than 5 ppm of HFO-1234ze(Z).

[0054] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant HFO-1234ze(E), wherein when administered using a metered dose inhaler or a breath actuated metered dose inhaler or a nebulizer, the fine particle fraction of the salbutamol or its enantiomer, or salt, or ester produced by the composition is at least 40.0% by weight of the delivered dose of the salbutamol or its enantiomer, or salt, or ester, even after the pharmaceutical composition has been stored at 50 °C and 75% relative humidity for 30, or 60, or 90, or 180 days.

[0055] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester and a pharmaceutically acceptable green propellant HFO-1234ze(E), wherein when administered using a metered dose inhaler or a breath actuated metered dose inhaler or a nebulizer, the fine particle fraction of the salbutamol or its enantiomer, or salt, or ester produced by the composition is at least 42% by weight of the delivered dose of the salbutamol or its enantiomer, or salt, or ester, even after the pharmaceutical composition has been stored at 50 °C and 75% relative humidity for 30, or 60, or 90, or 180 days, as compared to a composition comprising salbutamol or its enantiomer, or salt, or ester and a propellant HFA134a or HFA227ea.

[0056] In another embodiment, when administered using a metered dose inhaler or a breath actuated metered dose inhaler or a nebulizer, the composition produces the fine particle mass of salbutamol or its enantiomer, or salt, or ester with a smaller variability during the shelf life, having a relative standard deviation of less than 6.5%. In another embodiment, when administered using a metered dose inhaler or a breath actuated metered dose inhaler or a nebulizer, the composition produces the fine particle mass of salbutamol or its enantiomer, or salt, or ester with a smaller variability during the shelf life, having a relative standard deviation of less than 6.2%, as compared to a composition comprising salbutamol or its enantiomer, or salt, or ester and a propellant HFA134a or HFA227ea (wherein the relative standard deviation is greater than 7% or greater than 7.5%).

[0057] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant HFO-1234ze(E) as the sole propellant. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant HFO-1234ze(E) as the sole propellant. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant HFO-1234ze(E) as the sole propellant.

[0058] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, which is a combination of HFO-1234ze(E) and HFA134a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, which is a combination of HFO-1234ze(E) and HFA134a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, which is a combination of HFO-1234ze(E) and HFA134a.

[0059] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, which is a combination of HFO-1234ze(E) and HFA227ea. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, which is a combination of HFO-1234ze(E) and HFA227ea. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, which is a combination of HFO-1234ze(E) and HFA227ea.

[0060] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, and the propellant is a combination of HFO-1234ze(E) and HFA134a, wherein HFO-1234ze(E) is present at a concentration of 20% to 90% by weight of the composition, and HFA134a is present at a concentration of 20% to 90% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, and the propellant is a combination of HFO-1234ze(E) and HFA134a, wherein HFO-1234ze(E) is present at a concentration of 70% by weight of the composition, and HFA134a is present at a concentration of 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, and the propellant is a combination of HFO-1234ze(E) and HFA134a, wherein HFO-1234ze(E) is present at a concentration of 30% by weight of the composition, and HFA134a is present at a concentration of 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, and the propellant is a combination of HFO-1234ze(E) and HFA134a, wherein HFO-1234ze(E) is present at a concentration of 20% to 90% by weight of the composition, and HFA134a is present at a concentration of 20% to 90% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, and the propellant is a combination of HFO-1234ze(E) and HFA134a, wherein HFO-1234ze(E) is present at a concentration of 70% by weight of the composition, and HFA134a is present at a concentration of 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, and the propellant is a combination of HFO-1234ze(E) and HFA134a, wherein HFO-1234ze(E) is present at a concentration of 30% by weight of the composition, and HFA134a is present at a concentration of 70% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA134a, and wherein HFO-1234ze(E) is present at a concentration of 20% to 90% by weight of the composition, and HFA134a is present at a concentration of 20% to 90% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA134a, and wherein HFO-1234ze(E) is present at a concentration of 70% by weight of the composition, and HFA134a is present at a concentration of 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA134a, and wherein HFO-1234ze(E) is present at a concentration of 30% by weight of the composition, and HFA134a is present at a concentration of 70% by weight of the composition.

[0061] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA227ea. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA227ea. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA227ea.

[0062] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a, wherein HFO-1234ze(E) is present at a concentration of 20% to 90% by weight of the composition, and HFA-152a is present at a concentration of 20% to 90% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a, wherein HFO-1234ze(E) is present at a concentration of 70% by weight of the composition, and HFA-152a is present at a concentration of 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a, wherein HFO-1234ze(E) is present at a concentration of 30% by weight of the composition, and HFA-152a is present at a concentration of 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a, wherein HFO-1234ze(E) is present at a concentration of 20% to 90% by weight of the composition, and HFA-152a is present at a concentration of 20% to 90% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a, wherein HFO-1234ze(E) is present at a concentration of 70% by weight of the composition, and HFA-152a is present at a concentration of 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol tartrate and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a, wherein HFO-1234ze(E) is present at a concentration of 30% by weight of the composition, and HFA-152a is present at a concentration of 70% by weight of the composition.

[0063] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a. In the composition by weight, HFO-1234ze(E) is present at a concentration of 20% to 90%, and in the composition by weight, HFA-152a is present at a concentration of 20% to 90%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a. In the composition by weight, HFO-1234ze(E) is present at a concentration of 70%, and in the composition by weight, HFA-152a is present at a concentration of 30%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol hydrochloride and a pharmaceutically acceptable green propellant, wherein the propellant is a combination of HFO-1234ze(E) and HFA-152a. In the composition by weight, HFO-1234ze(E) is present at a concentration of 30%, and in the composition by weight, HFA-152a is present at a concentration of 70%.

[0064] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and a surfactant selected from oleic acid, polyvinylpyrrolidone of different K grades, lecithin, Tween 20, sorbitan trioleate, sorbitan monooleate, Tween 80, polyethylene glycol with a molecular weight of 200-1500, and combinations thereof. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 12 to 90.

[0065] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of 0.001% to 0.5% by weight of the composition. Alternatively, polyvinylpyrrolidone is present at the following concentrations by weight of the composition: 0.001%, or 0.003%, or 0.005%, or 0.01%, or 0.03%, or 0.05%, or 0.07%, or 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at the following concentrations: 0.005% to 0.2% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition; wherein HFA-152a is present at about 50% by weight of the composition, and HFO-1234ze(E) is present at about 50% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition; wherein HFA-152a is present at about 30% by weight of the composition, and HFO-1234ze(E) is present at about 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition; wherein HFA-152a is present at about 70% by weight of the composition, and HFO-1234ze(E) is present at about 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1% to about 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition.

[0066] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyethylene glycol having a level of 100 to 1000. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of 0.001% to 0.5% by weight of the composition. Alternatively, the polyethylene glycol is present at the following concentrations: 0.001%, or 0.003%, or 0.005%, or 0.01%, or 0.03%, or 0.05%, or 0.07%, or 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at the following concentrations: 0.005% to 0.2% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyethylene glycol having a grade of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyethylene glycol having a grade of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 50% by weight of the composition, and HFO-1234ze(E) is present at about 50% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyethylene glycol having a grade of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 30% by weight of the composition, and HFO-1234ze(E) is present at about 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride at about 0.1% to about 0.5% by weight, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyethylene glycol having a grade of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition.

[0067] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of 0.001% to 0.5% by weight of the composition. Alternatively, sorbitan trioleate or sorbitan monooleate is present at the following concentrations by weight of the composition: 0.001%, or 0.003%, or 0.005%, or 0.01%, or 0.03%, or 0.05%, or 0.07%, or 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at the following concentrations: 0.005% to 0.2% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein, based on the weight of the composition, sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein, based on the weight of the composition, sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein, based on the weight of the composition, sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005%; wherein, based on the weight of the composition, HFA-152a is present at about 50%, and, based on the weight of the composition, HFO-1234ze(E) is present at about 50%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein, based on the weight of the composition, sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005%; wherein, based on the weight of the composition, HFA-152a is present at about 30%, and, based on the weight of the composition, HFO-1234ze(E) is present at about 70%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein, based on the weight of the composition, sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005%; wherein, based on the weight of the composition, HFA-152a is present at about 70%, and, based on the weight of the composition, HFO-1234ze(E) is present at about 30%.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises from about 0.1% to about 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition.

[0068] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), a surfactant, and a solvent selected from ethanol, water, propanol, isopropanol, or a combination thereof. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and polyvinylpyrrolidone having a K value of 12 to 90 and ethanol. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of 0.001% to 0.5% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and ethanol, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at the following concentrations: 0.005% to 0.2% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 1% to 15% by weight, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 15% by weight, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 15% by weight, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% based on the weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% based on the weight of the composition; wherein HFA-152a is present at about 50% based on the weight of the composition, and HFO-1234ze(E) is present at about 50% based on the weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% based on the weight of the composition; wherein HFA-152a is present at about 30% based on the weight of the composition, and HFO-1234ze(E) is present at about 70% based on the weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride at about 0.1% to about 0.5% by weight, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyvinylpyrrolidone having a K value of 25; wherein polyvinylpyrrolidone is present at a concentration of about 0.005% based on the weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride at about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyvinylpyrrolidone having a K value of 25; wherein the polyvinylpyrrolidone is present at a concentration of about 0.005% based on the weight of the composition.

[0069] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol, and polyethylene glycol having a level of 100 to 1000. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol, and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of 0.001% to 0.5% by weight of the composition. Alternatively, the polyethylene glycol is present at the following concentrations: 0.001%, or 0.003%, or 0.005%, or 0.01%, or 0.03%, or 0.05%, or 0.07%, or 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 1% to 15% by weight, and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at the following concentrations: 0.005% to 0.2% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 15% by weight, and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 15% by weight, and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 15% by weight, and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyethylene glycol having a grade of 1000 or 400; wherein polyethylene glycol is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyethylene glycol having a grade of 1000 or 400; wherein polyethylene glycol is present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 50% by weight of the composition, and HFO-1234ze(E) is present at about 50% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyethylene glycol having a grade of 1000 or 400; wherein polyethylene glycol is present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 30% by weight of the composition, and HFO-1234ze(E) is present at about 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride at about 0.1% to about 0.5% by weight, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and polyethylene glycol having a grade of 1000 or 400; wherein polyethylene glycol is present at a concentration of about 0.1% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of salbutamol sulfate, or levosalbutamol tartrate, or levosalbutamol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), about 15% by weight of ethanol, and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of about 0.1% by weight of the composition.

[0070] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol, and sorbitan trioleate or sorbitan monooleate. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol in an amount of about 1% to 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of 0.001% to 0.5% based on the weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol in an amount of about 1% to 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at the following concentrations: 0.005% to 0.2% based on the weight of the composition, or 0.01% to 0.2% based on the weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol in an amount of about 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% based on the weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol in an amount of about 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% based on the weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol in an amount of about 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% based on the weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition; wherein HFA-152a is present at about 50% by weight of the composition, and HFO-1234ze(E) is present at about 50% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition; wherein HFA-152a is present at about 30% by weight of the composition, and HFO-1234ze(E) is present at about 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition; wherein HFA-152a is present at about 70% by weight of the composition, and HFO-1234ze(E) is present at about 30% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises from about 0.1% to about 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), about 15% by weight of ethanol, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), about 15% by weight of ethanol, and sorbitan trioleate or sorbitan monooleate; wherein sorbitan trioleate or sorbitan monooleate is present at a concentration of about 0.005% by weight of the composition.

[0071] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), polyvinylpyrrolidone having a K value of 12 to 90 and polyethylene glycol having a level of 100 to 1000. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), polyvinylpyrrolidone having a K value of 12 to 90 and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of 0.001% to 0.5% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), polyvinylpyrrolidone having a K value of 12 to 90 and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at the following concentrations: 0.005% to 0.2% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a level of 1000 or 400; wherein the polyvinylpyrrolidone and the polyethylene glycol are present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a level of 1000 or 400; wherein the polyvinylpyrrolidone and the polyethylene glycol are present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a level of 1000 or 400; wherein the polyvinylpyrrolidone and the polyethylene glycol are present at a concentration of about 0.1% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 50% by weight of the composition, and HFO-1234ze(E) is present at about 50% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 30% by weight of the composition, and HFO-1234ze(E) is present at about 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1% to about 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of salbutamol sulfate, or levosalbutamol tartrate, or levosalbutamol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a level of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition.

[0072] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol, polyvinylpyrrolidone having a K value of 12 to 90 and polyethylene glycol having a level of 100 to 1000. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol, polyvinylpyrrolidone having a K value of 12 to 90 and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at a concentration of 0.001% to 0.5% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 1% to 15% by weight, polyvinylpyrrolidone having a K value of 12 to 90 and polyethylene glycol having a level of 1000 or 400; wherein the polyethylene glycol is present at the following concentrations: 0.005% to 0.2% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 15% by weight, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a level of 1000 or 400; wherein the polyvinylpyrrolidone and the polyethylene glycol are present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 15% by weight, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a level of 1000 or 400; wherein the polyvinylpyrrolidone and the polyethylene glycol are present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol at about 15% by weight, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a level of 1000 or 400; wherein the polyvinylpyrrolidone and the polyethylene glycol are present at a concentration of about 0.1% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 50% by weight of the composition, and HFO-1234ze(E) is present at about 50% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 30% by weight of the composition, and HFO-1234ze(E) is present at about 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol at about 15% by weight, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 70% by weight of the composition, and HFO-1234ze(E) is present at about 30% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises from about 0.1% to about 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), about 15% by weight of ethanol, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% based on the weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises from about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), about 15% by weight of ethanol, polyvinylpyrrolidone having a K value of 25 and polyethylene glycol having a grade of 1000 or 400; wherein polyvinylpyrrolidone and polyethylene glycol are present at a concentration of about 0.1% based on the weight of the composition.

[0073] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and oleic acid. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and oleic acid; wherein oleic acid is present at a concentration of 0.001% to 0.5% by weight of the composition. Alternatively, the oleic acid is present at the following concentrations: 0.001%, or 0.003%, or 0.005%, or 0.01%, or 0.03%, or 0.05%, or 0.07%, or 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and oleic acid; wherein oleic acid is present at the following concentrations: 0.005% to 0.2% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and oleic acid; wherein oleic acid is present at a concentration of about 0.001% to about 0.3% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and oleic acid; wherein oleic acid is present at a concentration of about 0.03% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and oleic acid; wherein oleic acid is present at a concentration of about 0.03% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and oleic acid; wherein oleic acid is present at a concentration of about 0.03% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%; wherein, based on the weight of the composition, HFA-152a is present at about 50%, and, based on the weight of the composition, HFO-1234ze(E) is present at about 50%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%; wherein, based on the weight of the composition, HFA-152a is present at about 30%, and, based on the weight of the composition, HFO-1234ze(E) is present at about 70%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%; wherein, based on the weight of the composition, HFA-152a is present at about 70%, and, based on the weight of the composition, HFO-1234ze(E) is present at about 30%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1% to about 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%.

[0074] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol and oleic acid. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of 0.001% to 0.5%, and ethanol is present at a concentration of 1% to 15%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol and oleic acid; wherein oleic acid is present at the following concentrations: based on the weight of the composition, 0.005% to 0.2%, or based on the weight of the composition, 0.01% to 0.2%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.001% to about 0.3%, and ethanol is present at a concentration of 1% to 15%. Alternatively, oleic acid is present at the following concentrations: based on the weight of the composition, 0.001%, or 0.003%, or 0.005%, or 0.01%, or 0.03%, or 0.05%, or 0.07%, or 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%, and ethanol is present at a concentration of about 15%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%, and ethanol is present at a concentration of about 15%.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%, and ethanol is present at a concentration of about 15%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%, and ethanol is present at a concentration of about 15%; wherein, based on the weight of the composition, HFA-152a is present at about 50%, and, based on the weight of the composition, HFO-1234ze(E) is present at about 50%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%, and ethanol is present at a concentration of about 15%; wherein, based on the weight of the composition, HFA-152a is present at about 30%, and, based on the weight of the composition, HFO-1234ze(E) is present at about 70%. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises about 0.1% to about 0.5% by weight of salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%, and ethanol is present at a concentration of about 15%.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride in an amount of about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol and oleic acid; wherein oleic acid is present at a concentration of about 0.03% and ethanol is present at a concentration of about 15% by weight of the composition.

[0075] In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and magnesium stearate. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of 0.001% to 0.5% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at the following concentrations: 0.01% to 0.3% by weight of the composition, or 0.01% to 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.001% to about 0.2% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises levalbuterol, or its salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.1% by weight of the composition.In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 50% by weight of the composition, and HFO-1234ze(E) is present at about 50% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 30% by weight of the composition, and HFO-1234ze(E) is present at about 70% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.1% by weight of the composition; wherein HFA-152a is present at about 70% by weight of the composition, and HFO-1234ze(E) is present at about 30% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride in an amount of about 0.1% to about 0.5% by weight, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.1% by weight of the composition. In another embodiment, a pharmaceutical composition for inhalation is disclosed, which comprises salbutamol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride in an amount of about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5% by weight, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and magnesium stearate; wherein magnesium stearate is present at a concentration of about 0.1% by weight of the composition.

[0076] Also disclosed herein is a method for preparing such a composition. In one embodiment, the sedimentation rate of the active agent in the propellant medium depends on the method of preparing the composition. In another embodiment, the composition of the present invention is prepared by (1) a sonication process, or (2) a single-stage filling method, or (3) a two-stage filling method.

[0077] In a specific embodiment of the present invention, an active agent (salbutamol or its enantiomer, or salt, or ester) is mixed with a certain amount of a propellant (HFA-152a or HFO-1234ze(E)), or together with other excipients (such as ethanol, or PEG, or PVP). Then, the mixture is sonicated to obtain a stable suspension of the active agent in the propellant medium. Then, this stable suspension is filled into a can with a crimp valve, and the remaining part of the propellant can be added to a sufficient amount. In another embodiment, a homogenized slurry of the active agent, a certain amount of the propellant, and / or excipients (such as ethanol, PVP, PEG, oleic acid, etc.) are first mixed to obtain a homogenized slurry. This slurry can be mixed with the remaining excipients and then filled into a can with a crimp valve, and the remaining part of the propellant can be added to a sufficient amount.

[0078] In another embodiment, a sonication method is disclosed, which includes the following steps: (1) Weigh the required amount of the active agent (salbutamol or levalbuterol) in a standard 19 mL FCP-coated aluminum can (C0128, Presspart, Blackburn, UK), and crimp the can with a 63 μL valve, and (2) Then use a manual Pamasol crimper / filler (Pamasol, Switzerland) to fill the propellant or a mixture of propellants into the can through the valve. (3) Then fill the can with the required amount of the propellant. (4) Then sonicate the can for 60 minutes to ensure the dispersion of the active agent in the propellant medium. (5) The propellant can be added in the required amount or weight percentage sequence to obtain the final suspension composition.

[0079] In another embodiment, an ultrasonic treatment method is disclosed, which comprises the following steps: (1) weighing the required amount of the active agent (salbutamol or levalbuterol) in a standard 19 mL FCP-coated aluminum can (C0128, Presspart, Blackburn, UK), crimping a 63 μL valve to the can, and using a manual Pamasol valve sealer / filling machine (Pamasol, Switzerland), filling the propellant or a mixture of propellants, or sequentially added propellants, into the can through the valve; (2) then ultrasonically treating the can for 60 minutes to ensure the dispersion of the active agent in the propellant and / or excipient medium; (3) alternatively, the propellants can be sequentially added in the required amounts or weight percentages, wherein the excipient can be dissolved in one of the propellants and the mixture of the propellant and the excipient is filled first, followed by filling of additional propellants, to obtain a suspension composition; and (4) measuring the particle size of the suspension composition by conventional techniques in the art, and the particle size (MMAD D50) of salbutamol or levalbuterol in the composition is 3 to less than 5 microns (D50).

[0080] In another embodiment, an ultrasonic treatment method is disclosed, which comprises the following steps: (1) preparing a suspension composition containing salbutamol sulfate, ethanol, oleic acid, and HFA-152a or HFO-1234ze(E); (2) preparing a stock solution of ethanol and oleic acid, and directly weighing the ethanol solutions of salbutamol sulfate and oleic acid into a standard 19 mL aluminum can (C0128, Presspart, Blackburn, UK); (3) crimping a 63 μL valve to the can, and then using a manual Pamasol valve sealer / filling machine (Pamasol, Switzerland), filling HFA-152a or HFO-1234ze(E) into the can through the valve; (4) then ultrasonically treating the can for 60 minutes to ensure the dispersion of the active agent in the ethanol solution of oleic acid and the propellant medium. The final concentration of oleic acid in the preparation is 0.03 w / w. Some samples of Examples 14B and 14D are weighed in 24 mL plastic-coated glass bottles, and continuous valves are crimped. Then, using a manual Pamasol valve sealer / filling machine (Pamasol, Switzerland), the propellant is filled into the glass bottles through the valves; (5) ultrasonically treating the glass bottles for 60 minutes. Visual observations of the suspension characteristics of the glass bottles are evaluated. Thus, a suspension composition of salbutamol sulfate is obtained.

[0081] In another embodiment, a single-stage pressure filling for an ethanol-containing composition is disclosed. The steps include:

[0082] a) Dissolve oleic acid and ethanol in the propellant HFA-152a / HFO-1234ze(E) by homogenizing at a higher speed to obtain an ethanol solution of oleic acid. Transfer the homogenized solution to a mixing container containing a partial amount of the propellant.

[0083] b) Homogenize salbutamol sulfate with a partial amount of the propellant at a higher speed to obtain a homogenized slurry, and then transfer the homogenized slurry to the mixing container containing the ethanol solution of oleic acid obtained in step (a).

[0084] c) Further, mix the composition of step (b) with the remaining amount of the propellant at a speed of 150 - 300 rpm to obtain a homogenized suspension. Recycle the homogenized suspension through the filling line.

[0085] d) Crimp the valve onto the can and fill the suspension through the valve.

[0086] e) After filling the containers, quarantine them for valve stabilization.

[0087] In another embodiment, a two-stage pressure filling for ethanol-containing compositions is disclosed. The steps include:

[0088] a) Dissolve oleic acid and ethanol in the propellant HFA-152a / HFO-1234ze(E) by homogenizing at a higher speed, and transfer the homogenized solution to a mixing container containing a partial amount of the propellant.

[0089] b) Homogenize salbutamol sulfate with a partial amount of the propellant at a higher speed to obtain a homogenized slurry, and then transfer the homogenized slurry to the mixing container containing the ethanol solution of oleic acid from step (a).

[0090] c) Further, mix the composition of step (b) with the remaining amount of the propellant at a speed of 150 - 300 rpm. Recycle the homogenized suspension through the filling line.

[0091] d) Crimp the valve onto the can and fill the suspension through the valve.

[0092] e) Fill the propellant through the valve to supplement the volume according to the required filling volume.

[0093] f) After filling the containers, quarantine them for valve stabilization.

[0094] In another embodiment, a single-stage pressure filling of a dry formulation containing only the propellant is disclosed.

[0095] a) Homogenize salbutamol sulfate with a partial amount of the propellant at a higher speed to obtain a homogenized slurry, and then transfer the homogenized slurry to a mixing container containing a partial amount of the propellant.

[0096] b) Mix the remaining amount of the propellant at a speed of 150 - 300 rpm. Recirculate the homogenized suspension through the filling line.

[0097] c) Crimp the valve onto the can and fill the suspension through the valve.

[0098] d) After filling the containers, isolate them for valve stabilization.

[0099] In another embodiment, a two - stage pressure filling of a dry formulation containing only the propellant is disclosed.

[0100] a) Homogenize salbutamol sulfate with a partial amount of the propellant at a higher speed to obtain a homogenized slurry, and then transfer the homogenized slurry to a mixing container containing a partial amount of the propellant.

[0101] b) Mix with a partial amount of the propellant at a speed of 150 - 300 rpm. Recirculate the homogenized suspension through the filling line.

[0102] c) Crimp the valve onto the can and fill the suspension through the valve.

[0103] d) Fill the propellant through the valve to supplement the volume according to the required filling volume.

[0104] e) After filling the containers, isolate them for valve stabilization.

[0105] It was observed that the sedimentation rate of all formulations prepared with propellant HFA - 152a or HFO - 1234ze(E) was relatively better compared to propellant HFA - 134a. List information on the sedimentation rates prepared by ultrasonic treatment, single - stage and two - stage methods is given herein (Table 22).

[0106] In one embodiment, the sedimentation rate of the active agent with HFA - 152a or HFO - 1234ze(E) is greater than 30 seconds, or greater than 40 seconds, or greater than 60 seconds, or greater than 70 seconds, or greater than 80 seconds, or greater than 90 seconds, or greater than 1 minute, while the sedimentation rate of the active agent in the composition with HFA - 134a or HFA227ea is less than 30 seconds or less than 20 seconds.

[0107] The present invention further discloses a method for preventing or treating a respiratory disorder according to any embodiment of the present invention, wherein the respiratory disorder is selected from the group consisting of asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid - resistant asthma, severe asthma, childhood asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, and interstitial lung disease. In a further embodiment, the composition can be administered once or twice a day using a pMDI or BAI or nebulizer and following the approved label of albuterol or levalbuterol.

[0108] The present invention also discloses a method for administering the composition of the present invention for preventing or treating a respiratory disorder, wherein the respiratory disorder is selected from the group consisting of asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid - resistant asthma, severe asthma, childhood asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, and interstitial lung disease. In a further embodiment, the composition can be administered once or twice a day using a pMDI or BAI or nebulizer and following the approved label of albuterol or levalbuterol. The composition of the present invention conforms to any embodiment of the present invention.

[0109] The composition of the present invention prepared or disclosed herein is a stable composition, wherein the albuterol or its enantiomer, or salt, or ester remains stable during the shelf life. Specifically, the impurities in this stable composition remain well below the standard limits specified by the ICH guidelines.

[0110] The present invention is described in more detail by the following examples.

[0111] Examples

[0112] Example 1

[0113] Table 1

[0114]

[0115] Preparation method: Weigh the required amount of the active agent (salbutamol or levalbuterol) in a standard 19 mL FCP-coated aluminum can (C0128, Presspart, Blackburn, UK), and crimp a 63 μL valve onto the can. Then, using a manual Pamasol valve sealer / filler (Pamasol, Switzerland), fill the can with the propellant or a mixture of propellants through this valve. Then fill the can with the required amount of propellant. Then ultrasonically treat the can for 60 minutes to ensure the dispersion of the active agent in the propellant medium. The propellants can be added in the required amounts or weight percentages in sequence to obtain the final suspension composition. This method is used to prepare the compositions of Examples 1 to 9. The particle size of the suspension composition is determined by conventional techniques in the art. The particle size (MMAD D50) of salbutamol or levalbuterol in Compositions 1 to 9 is from 3 microns to less than 5 microns (D50).

[0116] Example 2

[0117] Table 2

[0118]

[0119] Example 3

[0120] Table 3

[0121]

[0122] Example 4

[0123] Table 4

[0124]

[0125] Example 5

[0126] Table 5

[0127]

[0128] Example 6

[0129] Table 6

[0130]

[0131] Example 7

[0132] Table 7

[0133]

[0134] Example 8

[0135] Table 8

[0136]

[0137] Example 9

[0138] Table 9

[0139]

[0140] Example 10

[0141] Table 10

[0142]

[0143] Preparation method:

[0144] HFA-134a is a very poor solvent and cannot dissolve useful concentrations of common surfactants such as sorbitan trioleate, sorbitan monooleate, lecithin, and oleic acid without the help of a co-solvent. Therefore, solubility studies were carried out with various surfactants / stabilizers (oleic acid, PVP, lecithin, Tween 20, sorbitan trioleate, sorbitan monooleate, Tween 80, PEG in the range of 200 - 1500 / viscosity regulator (glycerol) / organic acids (ascorbic acid, citric acid, malic acid) and inorganic acids (HCl, sulfuric acid, nitric acid), and visual observations were evaluated. Compared with the propellant HFA-134a, the evaluated excipients were found to be soluble in HFA-152a and HFO-1234ze(E). Solubility was evaluated with and without a co-solvent such as ethanol. It was found that the surfactants were soluble in the presence of ethanol at concentrations of 1% to 15%. First, the required amounts of excipients (PVP, ethanol, PEG, oleic acid, sorbitan trioleate, sorbitan monooleate, magnesium stearate) were weighed and dissolved in the propellant or a mixture of propellants (50 / 50% or 70 / 30% or 30 / 70%). The required amount of active ingredient (salbutamol or levalbuterol) was weighed in a standard 19 mL FCP-coated aluminum can (C0128, Presspart, Blackburn, UK), and the can was crimped with a 63 μL valve. Using a manual Pamasol valve sealer / filler (Pamasol, Switzerland), the propellant or a mixture of propellants, or the propellants added sequentially, was filled into the can through the valve. Then the can was sonicated for 60 minutes to ensure the dispersion of the active ingredient in the propellant and / or excipient medium. Alternatively, the propellants can be added sequentially in the required amounts or weight percentages, where the excipient can be dissolved in one propellant and the mixture of the propellant and the excipient is filled first, followed by the addition of additional propellants to obtain a suspension composition. This method was used to prepare the suspension compositions of Examples 9 to 12 and Examples 15 to 19. The particle size of the suspension composition was determined by conventional techniques in the art, and the particle size (MMAD D50) of salbutamol or levalbuterol in Compositions 1 to 8 was 3 microns to less than 5 microns (D50).

[0145] Example 11

[0146] Table 11

[0147]

[0148] Example 12

[0149] Table 12

[0150]

[0151] Example 13

[0152] Table 13

[0153]

[0154] Example 14

[0155] Table 14

[0156]

[0157] Preparation method:

[0158] Examples 14B and 14D: Suspension compositions containing salbutamol sulfate, ethanol, oleic acid, and HFA-152a or HFO-1234ze(E) were prepared. A stock solution of ethanol and oleic acid was prepared. The ethanol solution of salbutamol sulfate and oleic acid was directly weighed into a standard 19 mL aluminum can (C0128, Presspart, Blackburn, UK). The can was crimped with a 63 μL valve, and then HFA-152a or HFO-1234ze(E) was filled into the can through the valve using a manual Pamasol valve sealer / filler (Pamasol, Switzerland). The can was then sonicated for 60 minutes to ensure the dispersion of the active agent in the ethanol solution of oleic acid and the propellant medium. The final concentration of oleic acid in the formulation was 0.03 w / w. Some samples of Examples 14B and 14D were weighed into 24 mL plastic-coated glass bottles and crimped with a continuous valve. Then, the propellant was filled into the glass bottle through the valve using a manual Pamasol valve sealer / filler (Pamasol, Switzerland). The glass bottle was sonicated for 60 minutes. Visual observations were made to evaluate the suspension characteristics of the glass bottle. Thus, the suspension composition of salbutamol sulfate was obtained.

[0159] Examples 14A and 14C: The comparative composition in 14A was prepared according to the method of Example 1. Some samples of both 14A and 14C were filled into plastic-coated glass bottles crimped with a continuous valve for visual characterization. Thus, the suspension composition of salbutamol sulfate was obtained. Images of the glass bottles of Compositions 13A, B, C, and D are shown in Figure 1 in.

[0160] Example 15

[0161]

[0162] Example 15 was prepared according to the method described in Example 14.

[0163] Example 16

[0164] Table 16

[0165]

[0166] Example 17

[0167] Table 17

[0168]

[0169] Example 18

[0170] Table 18

[0171]

[0172] Example 19

[0173] Table 19

[0174]

[0175] Example 20

[0176] Table 20

[0177]

[0178] Example 21:

[0179] Using methods known in the art, such as an Anderson Cascade Impactor (ACI, Copley Scientific, Nottingham, UK) connected to a vacuum pump (Copley Scientific, Nottingham, UK), the pharmaceutical composition prepared according to Example 14 was visually and physicochemically characterized, such as determination of delivery dose uniformity and fine particle mass. For each experiment, four actuations of the canister were discharged into the ACI at 28.3 liters per minute according to pharmacopoeia guidelines. After aerosolization, the ACI device was disassembled and each part of the actuator and ACI was rinsed into a known volume of HPLC mobile phase. The mass of the drug deposited on each part of the ACI was determined by HPLC. The protocol was repeated for three canisters, and subsequently the fine particle mass (FPM) and the delivered dose were determined. The results are summarized in the table below.

[0180] Table 21

[0181]

[0182] *RSD: Relative Standard Deviation.

[0183] It is clear that Figure 1 visual observations show that the sedimentation rate of suspensions formulated with both HFA-152a and HFO-1234ze(E) is lower compared to the propellant HFA134a. Additionally, according to Table 21, suspensions formulated with the propellants HFA-152a and HFO-1234ze show a lower sedimentation rate compared to the propellant HFA134a. This helps to minimize variability, as is evident from the %RSD observed during the delivered dose uniformity and aerodynamic particle size distribution (APSD) tests. The change in the propellant has no effect on the target delivered dose uniformity and APSD.

[0184] Example 22: Alternative Methods for Preparing Propellant Compositions

[0185] To evaluate the performance of the sedimentation rate, suspensions of salbutamol sulfate were prepared using different preparation methods such as single-stage and two-stage filling.

[0186] Single-stage Pressure Filling - Ethanol Formulation

[0187] a) Oleic acid and ethanol were dissolved in the propellant HFA-152a / HFO-1234ze(E) by homogenizing at a higher speed to obtain an ethanol solution of oleic acid. The homogenized solution was transferred to a mixing container containing a partial amount of the propellant.

[0188] b) Salbutamol sulfate was homogenized with a partial amount of the propellant at a higher speed to obtain a homogenized slurry, and then the homogenized slurry was transferred to the mixing container containing the ethanol solution of oleic acid obtained in step (a).

[0189] c) Further, the composition of step (b) was mixed with the remaining amount of the propellant at a speed of 150 - 300 rpm to obtain a homogenized suspension. The homogenized suspension was recycled through the filling line.

[0190] d) The can was crimped with a valve, and the suspension was filled through the valve.

[0191] e) After filling the containers, they were isolated for valve stabilization.

[0192] Two-stage Pressure Filling - Ethanol Formulation

[0193] a) By homogenizing at a higher speed, dissolve oleic acid and ethanol in the propellant HFA-152a / HFO-1234ze(E), and transfer the homogenized solution to a mixing container containing a partial amount of the propellant.

[0194] b) Homogenize salbutamol sulfate with a partial amount of the propellant at a higher speed to obtain a homogenized slurry, and then transfer the homogenized slurry to the mixing container containing the ethanol solution of oleic acid from step (a).

[0195] c) Further, mix the composition of step (b) with the remaining amount of the propellant at a speed of 150 - 300 rpm. Recirculate the homogenized suspension through the filling line.

[0196] d) Crimp the valve onto the can, and fill the suspension through the valve.

[0197] e) Fill the propellant through the valve to supplement the volume according to the required filling volume.

[0198] f) After filling the container, isolate the valves for valve stabilization.

[0199] Single-stage pressure filling - dry preparation containing only the propellant.

[0200] a) Homogenize salbutamol sulfate with a partial amount of the propellant at a higher speed to obtain a homogenized slurry, and then transfer the homogenized slurry to the mixing container containing the ethanol solution of oleic acid.

[0201] b) Mix the remaining amount of the propellant at a speed of 150 - 300 rpm. Recirculate the homogenized suspension through the filling line.

[0202] c) Crimp the valve onto the can, and fill the suspension through the valve.

[0203] d) After filling the container, isolate the valves for valve stabilization.

[0204] Two-stage pressure filling - ethanol preparation

[0205] a) Homogenize salbutamol sulfate with a partial amount of the propellant at a higher speed to obtain a homogenized slurry, and then transfer the homogenized slurry to the mixing container containing the ethanol solution of oleic acid.

[0206] b) Mix with a partial amount of the propellant at a speed of 150 - 300 rpm. Recirculate the homogenized suspension through the filling line.

[0207] c) Crimp the valve onto the can, and fill the suspension through the valve.

[0208] d) Fill the propellant through the valve to replenish the volume according to the required filling volume.

[0209] e) After filling the containers, isolate them for valve stabilization.

[0210] Compared with the propellant HFA-134a, the sedimentation rate of all the preparations made with the propellants HFA-152a or HFO-1234ze(E) is relatively better. The following gives the list information of the sedimentation rates prepared by using the ultrasonic treatment, single-stage and two-stage methods (Table 22).

[0211] Table 22

[0212] Number Preparation Preparation method Sedimentation rate A Salbutamol sulfate / Oleic acid / Ethanol / HFA-152a Ultrasonic treatment method 32 seconds B Salbutamol sulfate / Oleic acid / Ethanol / HFA-152a Single-stage pressure filling 57 seconds C Salbutamol sulfate / Oleic acid / Ethanol / HFA-152a Two-stage pressure filling 65 seconds D Salbutamol sulfate / Oleic acid / Ethanol / HFO-1234ze(E) Ultrasonic treatment method 33 seconds E Salbutamol sulfate / Oleic acid / Ethanol / HFO-1234ze(E) Single-stage pressure filling 67 seconds F Salbutamol sulfate / Oleic acid / Ethanol / HFO-1234ze(E) Two-stage pressure filling 78 seconds G Salbutamol sulfate / HFO-1234ze(E) Ultrasonic treatment method 33 seconds H Salbutamol sulfate / HFO-1234ze(E) Single-stage pressure filling 63 seconds I Salbutamol sulfate / HFO-1234ze(E) Two-stage pressure filling 72 seconds J Salbutamol sulfate / HFA-134a Ultrasonic treatment method 7 seconds K Salbutamol sulfate / HFA-134a Single-stage pressure filling 10 seconds L Salbutamol sulfate / HFA-134a Two-stage pressure filling 12 seconds

Claims

1. A pharmaceutical composition for inhalation, which comprises salbutamol or its enantiomer, or salt, or ester, a pharmaceutically acceptable green propellant HFA-152a and / or HFO-1234ze(E), ethanol and oleic acid.

2. The pharmaceutical composition according to claim 1, wherein the oleic acid is present at a concentration of about 0.001% to about 0.5% by weight of the composition.

3. The pharmaceutical composition according to claim 2, wherein the oleic acid is present at a concentration of about 0.03% by weight of the composition.

4. The pharmaceutical composition according to claim 1, wherein the ethanol is present at a concentration of 1% to 15% by weight of the composition.

5. The pharmaceutical composition according to claim 4, wherein the ethanol is present at a concentration of about 15% by weight of the composition.

6. The pharmaceutical composition according to claim 1, wherein the composition is administered using a pressurized metered-dose inhaler, or a breath-actuated inhaler, or a nebulizer.

7. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a suspension or a solution.

8. The pharmaceutical composition according to claim 1, wherein salbutamol or its enantiomer, or salt, or ester is salbutamol base, salbutamol sulfate, levalbuterol base, or levalbuterol tartrate, or levalbuterol hydrochloride.

9. The pharmaceutical composition according to claim 8, wherein the salbutamol base or salbutamol sulfate is present at the following concentrations: 0.05% w / w to 1% w / w of the composition, or preferably 0.1% w / w to 0.5% w / w, or more preferably 0.2% w / w to 0.4% w / w.

10. The pharmaceutical composition according to claim 8, wherein the levalbuterol, or levalbuterol sulfate, or levalbuterol tartrate, or levalbuterol hydrochloride is present at the following concentrations: 0.05% w / w to 1% w / w of the composition, or preferably 0.1% w / w to 0.5% w / w, or more preferably 0.2% w / w to 0.4% w / w.

11. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable green propellant is HFA-152a.

12. The pharmaceutical composition according to claim 11, wherein HFA-152a is present in the composition at the following concentrations: at least 30% or 40% or 50% or 60% or 70% or 80% or 90% or 99%.

13. The pharmaceutical composition according to claim 12, wherein HFA-152a is present in the composition at a concentration of at least 90%.

14. The pharmaceutical composition according to claim 11, wherein based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of water.

15. The pharmaceutical composition according to claim 14, wherein based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of water.

16. The pharmaceutical composition according to claim 11, wherein, based on the total weight of the pharmaceutical composition, the composition contains less than 400 ppm of oxygen.

17. The pharmaceutical composition according to claim 16, wherein, based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of oxygen.

18. The pharmaceutical composition according to claim 11, wherein, based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of oxygen.

19. The pharmaceutical composition according to claim 11, wherein the propellant HFA-152a is greater than 90% or 95% or 99% or 99.5% or 99.99% pure and does not have any substantial impurities or contains no impurities.

20. The pharmaceutical composition according to claim 11, wherein the HFA-152a is the only propellant in the composition.

21. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable green propellant is HFO-1234ze(E).

22. The pharmaceutical composition according to claim 21, wherein the HFO-1234ze(E) is present in the composition at the following concentrations: at least 30% or 40% or 50% or 60% or 70% or 80% or 90% or 99%.

23. The pharmaceutical composition according to claim 22, wherein the HFO-1234ze(E) is present in the composition at a concentration of at least 90%.

24. The pharmaceutical composition according to claim 21, wherein, based on the total weight of the pharmaceutical composition, the composition contains less than 400 ppm of water.

25. The pharmaceutical composition according to claim 24, wherein, based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of water.

26. The pharmaceutical composition according to claim 21, wherein, based on the total weight of the pharmaceutical composition, the composition contains less than 1000 ppm of oxygen.

27. The pharmaceutical composition according to claim 26, wherein, based on the total weight of the pharmaceutical composition, the composition contains less than 1 ppm of oxygen.

28. The pharmaceutical composition according to claim 21, wherein, based on the total weight of the pharmaceutical composition, the composition contains less than 0.5 ppm of oxygen.

29. The pharmaceutical composition according to claim 21, wherein the propellant HFO-1234ze(E) is greater than 90% or 95% or 99% or 99.5% or 99.99% pure and does not have any substantial impurities or contains no impurities.

30. The pharmaceutical composition according to claim 29, wherein the propellant HFO-1234ze(E) contains less than 0.5 ppm to 10 ppm of unsaturated impurities or less than 0.25 ppm of unsaturated impurities.

31. The pharmaceutical composition according to claim 29, wherein the propellant HFO-1234ze(E) contains less than 10 ppm of HFO-1234ze(Z).

32. The pharmaceutical composition according to claim 231, wherein the propellant HFO-1234ze(E) contains less than 5 ppm of HFO-1234ze(Z).

33. The pharmaceutical composition according to claim 11, wherein, when administered using a metered-dose inhaler, the composition produces the fine particle mass of salbutamol or its enantiomer, or salt, or ester with less variability during shelf life compared to a composition comprising salbutamol or its enantiomer, or salt, or ester and the propellant HFA-134a or HFA-227ea, and has a relative standard deviation of less than 6%.

34. The pharmaceutical composition according to claim 21, wherein, when administered using a metered-dose inhaler, the composition produces the fine particle mass of salbutamol or its enantiomer, or salt, or ester with less variability during shelf life compared to a composition comprising salbutamol or its enantiomer, or salt, or ester and the propellant HFA-134a or HFA-227ea, and has a relative standard deviation of less than 6.5%.

35. A pharmaceutical composition for inhalation, which comprises salbutamol sulfate, or levalbuterol tartrate, or levosalbutamol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03%.

36. The pharmaceutical composition according to claim 35, wherein (a) based on the weight of the composition, HFA-152a is present at about 50% and, based on the weight of the composition, HFO-1234ze(E) is present at about 50%, or (b) based on the weight of the composition, HFA-152a is present at about 30% and, based on the weight of the composition, HFO-1234ze(E) is present at about 70%, or (c) based on the weight of the composition, HFA-152a is present at about 70% and, based on the weight of the composition, HFO-1234ze(E) is present at about 30%.

37. The pharmaceutical composition according to claim 35, wherein the composition further comprises ethanol and, based on the weight of the composition, the ethanol is present at a concentration of 1% to 15%.

38. The pharmaceutical composition according to claim 37, wherein, based on the weight of the composition, the ethanol is present at a concentration of about 15%.

39. A pharmaceutical composition for inhalation, which comprises salbutamol sulfate, or levalbuterol tartrate, or levosalbutamol hydrochloride, a pharmaceutically acceptable green propellant HFA-152a and HFO-1234ze(E), ethanol and oleic acid; wherein, based on the weight of the composition, oleic acid is present at a concentration of about 0.03% and ethanol is present at a concentration of about 15%.

40. The pharmaceutical composition according to claim 39, wherein (a) HFA-152a is present at about 50% by weight of the composition and HFO-1234ze(E) is present at about 50% by weight of the composition, or (b) HFA-152a is present at about 30% by weight of the composition and HFO-1234ze(E) is present at about 70% by weight of the composition, or (c) HFA-152a is present at about 70% by weight of the composition and HFO-1234ze(E) is present at about 30% by weight of the composition.

Images