Salbutamol delivery formulations, devices, and methods

Abstract

A pharmaceutical composition is disclosed comprising an active pharmaceutical ingredient (API) containing salbutamol, approximately 85% to approximately 99% by weight of HFO-1234ze(E), 1% to approximately 15% by weight of ethanol, and more than 0.01% to less than 0.1% by weight of oleic acid.

Description

Technical Field

[0001] (Cross - reference to related applications) This application is related to and claims priority to U.S. Provisional Patent Application No. 63 / 526,827, filed on June 14, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to drug delivery compositions, systems, devices, and methods. In certain embodiments, the present invention relates to pharmaceutical aerosol formulations, methods, and devices for the metered delivery of salbutamol (i.e., albuterol) or a pharmaceutically acceptable salt or ester thereof (e.g., salbutamol sulfate).

Background Art

[0003] Metered dose inhalers (MDIs) have been used for a long time to deliver drugs such as bronchodilators and steroids to the area of patients who need treatment. Compared with oral administration of bronchodilators, inhaler therapy using an MDI often has the advantages of a relatively rapid onset of action and a relatively low incidence of systemic side effects.

[0004] Asthma is described as a chronic disease characterized by inflammation and bronchial hyperresponsiveness of the pulmonary airways, leading to the clinical manifestation of lower airway obstruction, which is usually reversible. The pathophysiology of asthma or related disorders involves bronchoconstriction resulting from airway inflammation accompanied by bronchial smooth muscle spasms and mucosal edema. Treatment of asthma and other related disorders (including chronic obstructive pulmonary disease, COPD) involves the administration of β-2 agonists, also known as β-2 adrenergic receptor agonists. Such β-2 adrenergic receptor agonists are known to produce bronchodilation effects in patients and alleviate symptoms of dyspnea. More specifically, β-2 adrenergic receptor agonists have been shown to increase potassium channel conductance in airway muscle cells, leading to membrane hyperpolarization and relaxation. Salbutamol is a short-acting β-2 adrenergic receptor agonist that is recommended and used for the relief of acute asthma symptoms.

[0005] Medium-dose inhalation (MDI) is one of the most widely used systems for drug delivery by inhalation. The ultimate goal of an MDI is to deliver a specific, predetermined amount of drug to a patient's airway when activated by a person in need of relief, using a delivery composition in which the drug is dissolved, suspended, or dispersed. The delivery composition generally includes a propellant in addition to the active ingredient. For the propellant to function satisfactorily in an MDI, it must possess several properties. These include a suitable boiling point and vapor pressure such that it can liquefy in a sealed container at room temperature, but can generate sufficiently high pressure when the MDI is activated to deliver the drug as a spray formulation even at low ambient temperatures. Furthermore, the propellant must have low acute and chronic toxicity. The propellant should have a high degree of chemical stability in contact with the drug, container, and metallic and nonmetallic components of the MDI device, and should have a low tendency to extract low molecular weight substances from any elastomer materials in the MDI device. Preferably, the propellant can also maintain the drug in a homogeneous solution, a stable suspension, or a stable dispersion for a sufficient time to allow for reproducible delivery of the drug during use. When a drug is suspended in a propellant, the density of the liquid propellant should preferably be similar to that of the solid drug to avoid rapid settling or floating of drug particles in the liquid. Finally, the propellant should not pose a significant fire risk to the patient during use. In particular, the propellant should form a non-flammable or low-flammability mixture when mixed with air in the airway.

[0006] Propellants commonly used to date include mixtures of liquefied chlorofluorocarbons (CFCs) selected to have the vapor pressure necessary to generate the desired thrust, while also providing stability to the drug formulation and the other properties mentioned above. Methane and ethane-based CFCs such as tetrachloromethane (CFC-11), trichlorofluoromethane (CFC-12), and 1,2-dichlorotetrafluoroethane (CFC-114) are commonly used as propellants in aerosol formulations for inhalation administration.

[0007] The use of CFCs has environmental drawbacks. It is now known that CFCs react with the Earth's ozone layer, thereby tending to cause some degree of ozone depletion. As a result, various government and international organizations have engaged in efforts to reduce or eliminate the use of CFCs. The amount of CFCs used in conjunction with MDIs is considered small compared to other applications such as refrigerants and blowing agents. Nevertheless, potential ozone-depleting benefits can be achieved by reducing or eliminating CFCs from MDIs and other chemical delivery systems.

[0008] Due to the potential damage to the Earth's ozone layer caused by chlorine-containing compounds (such as chlorofluorocarbons (CFCs) and hydrochlorofluorocarbons (HCFCs)), there is a growing need for new fluorocarbon and hydrofluorocarbon compounds and compositions that offer alternatives with reduced potential for ozone depletion. For example, efforts are being made to replace chlorine-containing propellants with ozone-non-chlorine-containing compounds such as hydrofluorocarbons (HFCs).

[0009] U.S. Patent No. 5,776,434 (Purewal et al.) recognized the ozone depletion problem of CFCs and proposed the use of a non-chlorine-containing compound, namely 1,1,1,2-tetrafluoroethane (sometimes referred to herein as HFA-134a or HFC-134a), as a propellant for pharmaceutical aerosol formulations in combination with a surfactant and an adjuvant having higher polarity than 1,1,1,2-tetrafluoroethane. However, in 1998, the International Programme on Chemical Safety (IPCS) published the Concise International Chemical Assessment Document (No. 11), indicating that 1,1,1,2-tetrafluoroethane has significant potential to contribute to global warming.

[0010] HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane) has also been proposed as a low-ozone-depleting potential substitute for CFCs in MDI. However, this compound also has the potential to cause significant global warming.

[0011] U.S. Patent No. 9,308,199, assigned to the assignee of this application, describes the use of fluoroolefins, preferably hydrofluoroolefins (HFOs), as pharmaceutically acceptable carriers that can overcome the environmental deficiencies of the CFCs, HFCs, and HCFCs described above. Tetrafluoropropenes, including 1,3,3,3-tetrafluoropropene (HFO-1234ze) and 2,3,3,3-tetrafluoropropene (HFO-1234yf), are disclosed as preferred.

[0012] International Publication No. 2023 / 039103 states that HFO has been proposed as a propellant for MDI, but also points out that no MDI products using HFO as a propellant have been successfully developed or commercialized. Publication 103 discloses an MDI using a formulation comprising more than 70% by weight of HFO-1234ze(E), ethanol, and at least one active pharmaceutical ingredient (API).

[0013] Despite the foregoing disclosures, the applicant has recognized the need for delivery compositions, systems, devices, and methods of albuterol or its pharmaceutically acceptable salts or esters that simultaneously provide a relatively low ozone depletion potential, a relatively low global warming potential, and the ability to maintain the API in a homogeneous solution, a stable suspension, or a stable dispersion for a sufficient time to enable reproducible and accurate delivery of the drug in use. [Overview of the Initiative]

[0014] The applicants have found that the pharmaceutical compositions of the present invention, and their use in MDI and inhalation delivery methods, can overcome many of the shortcomings of conventional compositions and / or satisfy many of the above-mentioned needs.

[0015] The present invention also includes a pharmaceutical composition comprising the following: a. Active pharmaceutical ingredients (APIs) containing salbutamol, b. HFO-1234ze(E) in approximately 85% to 99% by weight, c. 1% to approximately 15% by weight of ethanol, d. Oleic acid in amounts greater than 0.001% by weight and less than 0.1% by weight.

[0016] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 1A.

[0017] The present invention also includes a pharmaceutical composition comprising the following: e. Active pharmaceutical ingredients (APIs) containing salbutamol, f. Approximately 85% to 99% by weight of HFO-1234ze(E), g. 1% to approximately 15% by weight of ethanol, Oleic acid in an amount greater than 0.005% by weight and less than 0.1% by weight.

[0018] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 1B.

[0019] The present invention also includes a pharmaceutical composition comprising the following: i. Active pharmaceutical ingredients (APIs) containing salbutamol, j. HFO-1234ze(E) in approximately 80% to 99% by weight, k. 1% to approximately 20% by weight of ethanol, 1. Oleic acid in an amount greater than 0.001% by weight and less than 0.1% by weight.

[0020] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 1C.

[0021] The present invention also includes a pharmaceutical composition comprising the following. m. An active pharmaceutical ingredient (API) comprising salbutamol, n. From about 90% to about 99% by weight of HFO-1234ze(E), o. From 1% to about 10% by weight of ethanol, and p. More than 0.001% to less than 0.1% by weight of oleic acid.

[0022] For convenience, the pharmaceutical composition according to this paragraph is referred to as pharmaceutical composition 1D.

[0023] <00000۹7>The present invention also includes a pharmaceutical composition comprising the following. q. An active pharmaceutical ingredient (API) comprising salbutamol, r. From about 95% to about 99% by weight of HFO-1234ze(E), s. From 1% to about 5% by weight of ethanol, and t. More than 0.001% to less than 0.1% by weight of oleic acid.

[0024] [[ID=۲۷]] For convenience, the pharmaceutical composition according to this paragraph is referred to as pharmaceutical composition 1E.

[0025] The present invention also includes a pharmaceutical composition comprising the following. a. An active pharmaceutical ingredient (API) comprising salbutamol, b. From about 85% to about 99% by weight of HFO-1234ze(E), c. From 1% to about 15% by weight of ethanol, d. More than 0.01% to less than 0.1% by weight of oleic acid.

[0026] For convenience, the pharmaceutical composition according to this paragraph is referred to as pharmaceutical composition 2A.

[0027] The present invention also includes a pharmaceutical composition comprising the following. a. An active pharmaceutical ingredient (API) comprising salbutamol, b. From about 80% to about 99% by weight of HFO-۱۲۳۴ze(E), c. From 1% to about 20% by weight of ethanol, and d. Oleic acid in amounts greater than 0.01% by weight and less than 0.1% by weight.

[0028] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 2B.

[0029] The present invention also includes a pharmaceutical composition comprising the following: a. Active pharmaceutical ingredients (APIs) containing salbutamol, b. Approximately 90% to 99% by weight of HFO-1234ze(E), c. 1% to approximately 10% by weight of ethanol, d. Oleic acid in amounts greater than 0.01% by weight and less than 0.1% by weight.

[0030] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 2C.

[0031] The present invention also includes a pharmaceutical composition comprising the following: a. Active pharmaceutical ingredients (APIs) containing salbutamol, b. Approximately 95% to 99% by weight of HFO-1234ze(E), c. 1% to approximately 5% by weight of ethanol, d. Oleic acid in amounts greater than 0.01% by weight and less than 0.1% by weight.

[0032] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 2D.

[0033] The present invention also includes a pharmaceutical composition comprising the following: u. Salbutamol-containing active pharmaceutical ingredient (API), v. Approximately 85% to 99% by weight of HFO-1234ze(E), w. 1% to approximately 15% by weight of ethanol, x.Oleic acid in amounts greater than 0.01% by weight and up to 0.05% by weight.

[0034] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 3A.

[0035] The present invention also includes a pharmaceutical composition comprising the following: y. Salbutamol-containing active pharmaceutical ingredient (API), z. HFO-1234ze(E) in approximately 80% to 99% by weight. aa. 1% to approximately 20% by weight of ethanol, bb.Oleic acid in amounts greater than 0.01% by weight and up to 0.05% by weight.

[0036] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 3B.

[0037] The present invention also includes a pharmaceutical composition comprising the following: cc. Salbutamol-containing active pharmaceutical ingredient (API), dd. Approximately 90% to 99% HFO-1234ze(E), ee. 1% to approximately 10% by weight of ethanol, ff.Oleic acid in amounts exceeding 0.01% by weight and up to 0.05% by weight.

[0038] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 3C.

[0039] The present invention also includes a pharmaceutical composition comprising the following: gg. Salbutamol-containing active pharmaceutical ingredients (APIs), HH. Approximately 95% to 99% HFO-1234ze(E), ii. Ethanol in an amount of 1% to approximately 5% by weight, and Oleic acid in a concentration of over 0.01% by weight and up to 0.05% by weight.

[0040] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 3D.

[0041] The present invention also includes a pharmaceutical composition comprising the following: kk. Salbutamol, an active pharmaceutical ingredient (API), ll. Approximately 80% to 99% HFO-1234ze(E), 1 mm by weight to approximately 10 mm by weight of ethanol, Oleic acid in amounts exceeding 0.01% by weight and up to 0.05% by weight.

[0042] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 3B.

[0043] The present invention also includes a pharmaceutical composition comprising the following: oo. Active pharmaceutical ingredients (APIs) containing salbutamol, pp. Approximately 85% to 96.5% by weight of HFO-1234ze(E), Ethanol in an amount of 3.5% to approximately 15% by weight, and Oleic acid in a concentration of more than 0.005% by weight and less than 0.1% by weight.

[0044] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 4.

[0045] The present invention also includes a pharmaceutical composition comprising the following: ss. Salbutamol-containing active pharmaceutical ingredient (API), tt. HFO-1234ze(E) in approximately 85% to 96.5% by weight. 3.5% to approximately 15% by weight of ethanol, and Oleic acid in amounts greater than 0.01% by weight and less than 0.1% by weight.

[0046] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 5.

[0047] The present invention also includes a pharmaceutical composition comprising the following: Active pharmaceutical ingredient (API) containing salbutamol, xx. HFO-1234ze(E) in approximately 85% to 96.5% by weight. Ethanol in an amount of approximately 3.5% to 15% by weight, and Oleic acid in an amount of over 0.01% by weight to 0.05% by weight.

[0048] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 6.

[0049] The present invention also includes a pharmaceutical composition comprising the following: aaa. Active pharmaceutical ingredient (API) containing salbutamol, bbb. Approximately 85% to 90% by weight of HFO-1234ze(E), ccc. 10% to approximately 15% by weight of ethanol, Oleic acid in amounts greater than 0.005% by weight and less than 0.1% by weight.

[0050] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 7.

[0051] The present invention also includes a pharmaceutical composition comprising the following: eee. Salbutamol is an active pharmaceutical ingredient (API). fff. Approximately 85% to 90% by weight of HFO-1234ze(E), ggg.10% to approximately 15% by weight of ethanol, and hhh.Oleic acid in amounts greater than 0.01% by weight and less than 0.1% by weight.

[0052] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 8.

[0053] The present invention also includes a pharmaceutical composition comprising the following: iii. Active pharmaceutical ingredients (APIs) containing salbutamol, jjj. HFO-1234ze(E) in approximately 85% to 90% weight, kkk. 10% to approximately 15% by weight of ethanol, 3. Oleic acid in amounts exceeding 0.01% by weight and up to 0.05% by weight.

[0054] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 9.

[0055] The present invention also includes a pharmaceutical composition comprising the following: mmm. Salbutamol is an active pharmaceutical ingredient (API), Approximately 85% by weight of HFO-1234ze(E), ooo. Approximately 15% by weight of ethanol, and Oleic acid in amounts greater than 0.005% by weight and less than 0.1% by weight.

[0056] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 10.

[0057] The present invention also includes a pharmaceutical composition comprising the following: qqq. Active pharmaceutical ingredient (API) containing salbutamol, rrr. Approximately 85% by weight of HFO-1234ze(E), SSS. Approximately 15% by weight of ethanol, and Oleic acid in amounts greater than 0.01% by weight and less than 0.1% by weight.

[0058] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 11.

[0059] The present invention also includes a pharmaceutical composition comprising the following: uuu. Active pharmaceutical ingredients (APIs) containing salbutamol, vvv. Approximately 90% by weight of HFO-1234ze(E), www. Approximately 10% by weight of ethanol, and xxx.Oleic acid in a concentration of over 0.01% by weight and up to 0.05% by weight.

[0060] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 12.

[0061] The present invention also includes a pharmaceutical composition comprising the following: yyy. Active pharmaceutical ingredient (API) containing salbutamol, zzz. HFO-1234ze(E) at approximately 85% to less than 95% by weight, and aaaa. Ethanol exceeding 5% by weight to approximately 15% by weight.

[0062] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 13.

[0063] The present invention also includes a pharmaceutical composition comprising the following: bbbb. Active pharmaceutical ingredient (API) containing salbutamol, cccc. Approximately 85% by weight of HFO-1234ze(E), and Approximately 15% by weight of ethanol.

[0064] For convenience, the pharmaceutical composition described in this paragraph will be referred to as pharmaceutical composition 14. [Brief explanation of the drawing]

[0065] Next, the present invention will be described with reference to the accompanying drawings. [Figure 1] This is a side cross-sectional view of an inhaler including a canister with a valve according to the present disclosure. [Figure 2] Figure 1 is a detailed side cross-sectional view of the inhaler. [Figure 3] This is a side cross-sectional view of a metering valve for an inhaler. [Figure Ex2A] This chart shows the data from Example 2. [Figure Ex2B] This chart shows the data from Example 2. [Figure ExC3] This chart shows the data from Comparative Example 3. [Figure Ex3] This chart shows the data from Example 3. [Figure Ex4A] This chart shows the data from Example 4. [Figure Ex4B] This chart shows the data from Example 4. [Figure Ex4C] This chart shows the data from Example 4. [Figure Ex5] This chart shows the data from Example 5. [Modes for carrying out the invention]

[0066] I. Definition For the purposes of this invention, with respect to amounts expressed as weight percent for amounts exceeding 2%, the term "about" means that the amount of the component may vary by + / - 2% by weight.

[0067] For the purposes of this invention, with respect to amounts expressed as weight percent for amounts less than 2% and greater than 1%, the term "about" means that the amount of the component may vary by + / - 1 weight percent.

[0068] For the purposes of this invention, the term "about" with respect to amounts expressed as weight percent for amounts less than 1% and greater than 0.5% means that the amount of the component may vary by + / - 0.2% by weight.

[0069] For the purposes of this invention, the term "about" with respect to amounts expressed as weight percent for amounts less than 0.5% means that the amount of the component may vary by + / - 0.05% by weight.

[0070] For the purposes of this invention, the term "approximately" in relation to Celsius temperature (°C) means that the stated temperature may vary by an amount of + / - 5°C.

[0071] The terms "HFC-134a" and "R134a" refer to 1,1,1,2-tetrafluoroethane.

[0072] As used herein, the terms "HFO1234ze(E)", "R1234ze(E)", and "1234ze(E)" mean trans-1,3,3,3-tetrafluoropropene. Unless otherwise specified, "HFO1234ze", "R1234ze", and "1234ze" mean trans-1,3,3,3-tetrafluoropropene.

[0073] As used herein, the term “salbutamol” encompasses any and all pharmaceutically acceptable versions of salbutamol, including salts of salbutamol.

[0074] As used herein, the term “salbutamol sulfate” encompasses any and all pharmaceutically acceptable versions of salbutamol sulfate.

[0075] References herein to a defined group of items include all such defined items, including all such items that have a suffix designation.

[0076] II. Composition A preferred pharmaceutical composition of the present invention, comprising each of pharmaceutical formulations 1 to 14, is a stable suspension or dispersion of APIs in a carrier containing other necessary components of the formulation, particularly HFO-1234ze(E) and ethanol.

[0077] A. Concentration of ingredients The concentrations of the components in the compositions of the present invention can generally vary widely within the broad range of the present invention. The concentration of the API contained in the compositions of the present invention, each comprising pharmaceutical formulations 1 to 14, is preferably 0.0008% to 3.4% by weight, or 0.01% to 1.0% by weight, or 0.05% to 0.5%. Preferred compositions include those specified in Table 1 below, all numbers are understood to be preceded by "approximately", and the following symbols in the table have the following meanings: "comp" means that the formulation contains the specified component. CEO means that the formulation consists essentially of the specified component. CO means that the formulation consists of the specified component. TSI means the turbidity stability index at 30 seconds, determined according to the examples herein, and NR means that the component is not required to be present.

[0078] [Table 1-1]

[0079] [Table 1-2]

[0080] [Table 1-3]

[0081] [Table 1-4]

[0082] For all compositions of the present invention, except those defined as "consisting of" the specified components, including each of pharmaceutical compositions 1 to 32, salbutamol contains salbutamol sulfate, or is essentially composed of salbutamol sulfate, or consists of salbutamol sulfate.

[0083] In all compositions of the present invention, in addition to those defined as "consisting of" the specified components, each of the pharmaceutical compositions 1 to 32, additional components or excipients may be present. These components may have a variety of uses and functions, including, but not limited to, facilitating the formation of suspensions, stabilizing suspensions, and / or assisting in the chemical stabilization of APIs or other components.

[0084] For all compositions of the present invention, including each of pharmaceutical compositions 1 to 32, the composition comprises a “suspension” or “dispersion” of the indicated API in HFO-1234ze(E) and ethanol, and, if present, oleic acid. In all such compositions, including each of pharmaceutical compositions 1 to 32, the designated API is in particulate solid form (preferably pulverized, but its size can be reduced by a number of other particle size reduction techniques). As used herein, the suspension / dispersion of the API contains particles of the API that have a visual effect on the human eye, although small amounts of solubilized particulate matter may be present in the composition. For suspension formulations, including each of pharmaceutical formulations 1 to 32, solubilization of the API is generally undesirable. In embodiments, including each of pharmaceutical formulations 1 to 32, solubilization of the API is minimal, and in some preferred embodiments, including each of pharmaceutical formulations 1 to 32, solubilization of the API is essentially absent.

[0085] The preferred pharmaceutical compositions of the present invention, each comprising pharmaceutical formulations 1 to 32, have a certain degree of physical stability that avoids significant separation of the physical mixture due to sedimentation or creaming of suspended / dispersed particles.

[0086] In a particular preferred form, the compositions of the present invention comprising each of pharmaceutical compositions 1 to 32 have a Global Warming Potential (GWP) of about 1500 or less, more preferably about 75 or less, and even more preferably about 10 or less. As used herein, “GWP” is measured over a 100-year planned period relative to the GWP of carbon dioxide, as defined in “The Scientific Assessment of Ozone Depletion, 2002, a report of the World Meteorological Association’s Global Ozone Research and Monitoring Project,” which is incorporated herein by reference.

[0087] In certain preferred embodiments, the compositions of the present invention also have an ozone depletion potential (ODP) of preferably 0.05 or less, more preferably 0.02 or less, and even more preferably about 0. As used herein, “ODP” is as defined in “The Scientific Assessment of Ozone Depletion, 2002, A report of the World Meteorological Association’s Global Ozone Research and Monitoring Project,” which is incorporated herein by reference.

[0088] Many embodiments of the present invention, comprising each of pharmaceutical compositions 1 to 32, particularly embodiments in which the composition is in the form of a suspension, emulsion, or dispersion, preferably include a stabilizer. Stabilizers for such suspensions, emulsions, and dispersions are well known, and all such stabilizers are intended to be adaptable to use according to the present invention. Exemplary stabilizers include, either alone or in combination, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid, benzalkonium chloride, ethylenediaminetetraacetic acid, and pharmaceutically acceptable salts thereof. While the stabilizers of the present invention are intended to be present in a wide range of amounts in the composition, in many embodiments, the stabilizer is generally preferred to be present in an amount of about 40 to about 100 ppm by weight of the composition.

[0089] III. Devices and Methods The present invention includes a device for delivering compositions of the present invention, each comprising one of the pharmaceutical compositions 1 to 32, by inhalation. In a particular preferred embodiment, the device of the present invention comprises a pressurized formulation of the present invention, each comprising one of the pharmaceutical compositions 1 to 32, and preferably a container (preferably an aerosol canister) having a metering and dispensing valve operable between a non-dispensing position and a dispensing position. The device also preferably comprises an actuator, which in a preferred embodiment comprises a housing adapted to receive the aerosol container and preferably in the form of a mouthpiece and / or nasal adapter, defining a chamber that fluidly communicates with a patient port for introducing the drug into the oral and / or nasal cavity of a patient. The actuator also preferably comprises a nozzle block adapted to receive the valve stem of the dispensing valve, which preferably comprises a passage that fluidly communicates with the valve stem and terminates with an opening for directing the drug from the valve stem into the chamber.

[0090] As an example, but not an limitation, Figure 1 shows one embodiment of a metering inhaler 100, which includes an aerosol canister 1 to which a metering valve 10 (shown in its resting position) is attached. The metering valve 10 is typically attached, i.e., crimped onto the canister via a cap or ferrule 11 (typically made of aluminum or an aluminum alloy), which is commonly provided as part of a valve assembly. One or more seals may be present between the canister and the ferrule. In the embodiments shown in Figures 1 and 2, there are two seals between the canister 1 and the ferrule 11, including, for example, an O-ring seal and a gasket seal.

[0091] As shown in Figure 1, a canister / valve dispenser typically comprises an actuator 5 including a suitable patient port 6, such as a mouthpiece. For nasal administration, the patient port is generally provided in a suitable form for delivery through the nose (e.g., a smaller diameter tube, often angled upward). The actuator is generally made of a plastic material, such as polypropylene or polyethylene. As can be seen from Figure 1, the inner wall 2 of the canister and the outer wall 101 of the portion(s) of the metering valve 10 located within the canister define a formulation chamber 3 in which the aerosol formulation 4 is contained.

[0092] The valve 10 shown in Figures 1 and 2 includes a metering chamber 12 partially defined by an inner valve body 13, through which a valve stem 14 passes. The valve stem 14, biased outward by a compression spring 15, is in sliding seal engagement with an inner tank seal 16 and an outer diaphragm seal 17. The valve 10 also includes a second valve body 20 in the form of a bottle empty. The inner valve body 13 (also called the “primary” valve body) partially defines the metering chamber 12. The second valve body 20 (also called the “secondary” valve body) partially defines the pre-metering area or chamber in addition to functioning as a bottle empty.

[0093] Referring to Figure 2, the aerosol formulation 4 can enter the pre-metering chamber 22 located between the secondary valve body 20 and the primary valve body 13, through the annular space 21 between the flange 23 of the secondary valve body 20 and the primary valve body 13, from the formulation chamber 3. To activate (fire) the valve 10, the valve stem 14 is pushed inward relative to the canister 1 from its resting position shown in Figures 1 and 2, allowing the formulation to exit from the metering chamber 12 through the side hole 19 of the valve stem, through the stem outlet 24 to the actuator nozzle 7, and then to the patient. When the valve stem 14 is released, the formulation enters the valve 10, particularly the pre-metering chamber 22, through the annular space 21, and from the pre-metering chamber through the groove 18 in the valve stem, through the tank seal 16, and into the metering chamber 12.

[0094] Figure 3 shows another embodiment of the metering aerosol metering valve 102, different from the embodiments shown in Figures 1 and 2, in its resting position. The valve 102 has a metering chamber 112 partially defined by a metering tank 113, and a stem 114 is biased outward by a spring 115 through the metering chamber. The stem 114 is made of two parts that are press-fitted together before being assembled into the valve 102. The stem 114 has an inner seal 116 and an outer seal 117 arranged around the stem and forming a sealed contact with the metering tank 113. The valve body 120, crimped within a ferrule 111, holds the aforementioned components within the valve. When in use, the formulation enters the metering chamber through openings 121 and 118. The outer path of the formulation from the metering chamber 112 when the dose is dispensed is through opening 119.

[0095] In certain embodiments, the device of the present invention is constructed such that the airflow due to patient inhalation is prevented or reduced near the opening, either at all times or only during drug distribution from the valve. Any such configuration has the effect of substantially reducing the rate of the spray discharged compared to inhalers that allow free airflow near the nozzle block during drug distribution.

[0096] In certain embodiments, the actuator is configured such that the distance from the nozzle to the mouthpiece is approximately 1 to 15 cm, preferably 4 to 6 cm, and the diameter of the chamber / mouthpiece is 1 to 4 cm, or 0.5 to 1 cm in the case of a nasal adapter.

[0097] In certain preferred but non-limiting embodiments, the actuator has an air inlet that allows the patient to inhale through the patient port without encountering significant resistance, preferably because the patient may have difficulty breathing when taking medication, for example, during an asthma attack. However, the air inlet in the mouthpiece, for example, preferably does not concentrate the airflow in an area that is too narrow, because this would provide a high-velocity incoming air that deflects the spray onto the mouthpiece wall opposite the air inlet. In certain preferred embodiments, the air inlet is located downstream of the nozzle, within the turbulence zone, and / or downstream of the turbulence zone. The position and orientation of the air inlet can also affect drug deposition in the chamber and mouthpiece. In one configuration, the air inlet includes a series of holes that can optionally be interdispersed with fluid deflection structures on the chamber wall to guide air into the turbulence zone and mix the air with the aerosol flow. Furthermore, the mouthpiece may be made of a porous material to allow a number of finely divided vents to provide airflow over a larger surface area.

[0098] In certain embodiments, the actuator has an air inlet upstream of or near the nozzle, but the air inlet is closed when the valve is fired and the aerosol spray is released. The air inlet is opened after the spray has been released, by which time the flow velocity has decreased and a turbulent zone has been formed. During inhalation, an airflow is established from the air inlet to the mouthpiece, which entrains the residual aerosol spray. The actuator may include an additional air inlet downstream of the nozzle, as described above with respect to the first embodiment. These downstream air inlets do not need to be closed during the release of the aerosol spray.

[0099] In certain embodiments, a porous membrane is present to introduce air into or downstream of the turbulent zone. One advantage of using such a membrane is that the air is introduced more uniformly and diffusely around the atom, thereby acting as a buffer between the turbulence and the wall. The effect is to reduce drug deposition within the device. The membrane may optionally be protected from contamination or contact by the user's lips by an additional part of the mouthpiece. If present, it is preferable that the porous membrane material (50) does not significantly impede the patient's ability to inhale through the device. A suitable material is Whatman No. 4 filter paper. However, other materials may be used, such as those used in cylindrical air filters or membrane filters, or those formed by sintered polymers. A preferred porous membrane material is in the form of a cylinder made by fusing together small pellets of polypropylene.

[0100] For certain medications, it is preferable to configure the device to reduce contact between the medication and parts of the patient's body that are not intended to come into contact with it. For example, medication residue deposited on the inner surface of the actuator may be touched with a finger and transferred to other parts of the body. In such cases, the device may be configured to include one or more fluid flow deflectors to restrict patient access to the inner surface of the actuator while allowing the spray to pass through. Of course, the device may also be configured for intranasal delivery. This is usually undesirable because the medication is designed for delivery to the respiratory system and may not have the appropriate effect if it is allowed to deposit in the oropharynx and enter the gastrointestinal tract. In an attempt to overcome this problem, certain embodiments of the device provide a retaining volume, commonly called a spacer, into which the medication is ejected. The spacer can preferably reduce the velocity of the medication and may also allow some evaporation of propellant. The spacer can improve the performance of the metering inhaler by reducing oropharyngeal deposits.

[0101] The total amount of the composition of the present invention, including each of pharmaceutical compositions 1 to 32, contained in the canister is preferably selected such that at least a portion of the propellant in the canister remains in liquid form after a predetermined number of pharmaceutical doses have been delivered. The predetermined number of doses may be 5 to 200, 30 to 200, 60 to 200, 60 to 120, 60, 120, 200, or any other number of doses. In a preferred embodiment, the total amount of the composition of the present invention, including each of pharmaceutical compositions 1 to 32, contained in the canister may be 1.0 g to 30.0 g, 2.0 g to 20.0 g, or 5.0 to 10.0 g. The total amount of the composition of the present invention, including each of pharmaceutical compositions 1 to 32, is typically selected to be greater than the product of the predetermined number of doses and the metering volume of the metering valve. In some embodiments, the total amount of the composition is greater than 1.1, 1.2, 1.3, 1.4, or 1.5 times the product of the number of doses and the volume measured by the measuring valve. This helps to ensure that each dose remains relatively constant throughout the life of the inhaler.

[0102] Accordingly, the present invention provides an inhaler, preferably a medium-dose inhaler (MDI), for the treatment of asthma and other chronic obstructive pulmonary diseases, and for the delivery of pharmaceutical compositions, each of the pharmaceutical compositions 1 to 32, into an accessible mucous membrane or nasal cavity. Accordingly, the present invention includes a method for delivering pharmaceutical compositions, each of the pharmaceutical compositions 1 to 32, for the purpose of treating diseases, disorders, and similar health-related problems in organisms (e.g., humans or animals), the method comprising applying the composition of the present invention, which contains a drug or other therapeutic component, to an organism in need of treatment. In a particular preferred embodiment, the step of applying the composition of the present invention includes providing an MDI containing the composition of the present invention, each of the pharmaceutical compositions 1 to 32, and then releasing the composition of the present invention from the MDI.

[0103] The amount of API delivered may be determined by the required dose per operation and the MDI metering valve size, i.e., the size of the metering chamber, which may be 5 microliters (μL or mcl) to 200 microliters, 25 microliters to 200 microliters, 25 microliters to 150 microliters, 25 microliters to 100 microliters, or 25 microliters to 65 microliters.

[0104] In some embodiments, a typical formulation of the Disclosure comprises at least 0.001 milligrams (mg / action) (1 microgram (μg) per action), or at least 0.01 mg / action (10 μg / action) of API per action. In certain embodiments, a typical formulation of the Disclosure comprises less than 0.5 mg / action (500 pg / action) of API.

[0105] In embodiments, a typical formulation of the Disclosure includes an API in an amount of at least 1 μg / acting, at least 10 μg / acting, at least 50 μg / acting, at least 100 μg / acting, at least 150 μg / acting, at least 200 μg / acting, at least 300 μg / acting, or at least 400 μg / acting. In embodiments, a typical formulation of the Disclosure includes an API in an amount of less than 500 μg / acting, up to 400 μg / acting, up to 300 μg / acting, or up to 200 μg / acting. In some preferred embodiments, a formulation of the Disclosure includes an API in an amount of 80 μg / acting to 200 μg / acting.

[0106] The present invention also includes a method for forming a pharmaceutical composition having improved stability, comprising each of pharmaceutical compositions 1 to 32, comprising forming a carrier comprising 99% by weight or less of HFO-1234ze and more than about 0% by weight to less than about 10% by weight of ethanol, and suspending an API comprising salbutamol, essentially therefor, or composed thereof, in the carrier, wherein the suspension has an improved migration rate compared to a carrier comprising more than about 10% of ethanol. The present invention also includes a method for forming a pharmaceutical composition having improved stability, comprising each of pharmaceutical compositions 1 to 32, comprising forming a carrier comprising 99% by weight or less of HFO-1234ze and more than about 0% by weight to less than about 10% by weight of ethanol, and suspending an API comprising 0.25% by weight to about 0.5% by weight of salbutamol, essentially therefor, or composed thereof, in the carrier, wherein the suspension has an improved migration rate compared to a carrier comprising more than about 10% of ethanol.

[0107] The present invention provides a method for forming a pharmaceutical composition having improved stability, comprising each of pharmaceutical compositions 1 to 32, comprising forming a carrier containing 95% by weight or less and more than 5% by weight to about 15% by weight of ethanol, and suspending an API containing, essentially having, or comprising salbutamol in the carrier, wherein the suspension has improved TSI compared to a carrier containing 2.5% by weight or less of ethanol.

[0108] The present invention provides a method for forming a pharmaceutical composition having improved stability, comprising each of pharmaceutical compositions 1 to 32, comprising forming a carrier containing 95% by weight or less and more than about 5% by weight to about 15% by weight of ethanol, and suspending an API containing 0.25% by weight to about 0.5% by weight of salbutamol, or essentially thereof, in the carrier, wherein the suspension has an improved TSI compared to a carrier containing 2.5% by weight or less of ethanol. [Examples]

[0109] Comparative Example 1: Delivery dose of salbutamol sulfate suspension in 100% HFO-1234ze(E) and in a mixture of 95% HFO-1234ze(E) and 5% ethanol. Salbutamol sulfate (API) was suspended in HFC-1234ze(E) and a mixture of HFC-1234ze(E) and ethanol in the amounts shown in Table C1 below. Each formulation was then loaded into an MDI with a target dose delivery of 167 micrograms per action, and tested to determine the Average Delivered Dose Uniformity (ADDU) and the standard deviation of ADDU (generally following the guidelines described in USP601 - Inhalation and Nasal Drug Products: Aerosol, Spray, and Powder Performance Testing). The results of this test are reported in Table ExC1 below.

[0110] [Table 2]

[0111] As can be seen from the test results reported in Table ExC1 above, the use of a carrier containing 100% HFO-1234ze(E), and a carrier containing approximately 95% HFO-1234ze(E) and 5% ethanol, respectively, produced ADDU within a favorable range of + / -25%. However, in each case, the standard deviation of the results was unacceptably high, i.e., at a standard deviation level of 45%.

[0112] Example 1: Delivery dose of salbutamol sulfate suspension in 85% HFO-1234ze(E) and 15% ethanol Salbutamol sulfate (API) was suspended in a mixture of approximately 85% by weight HFO-1234ze(E) and 15% by weight ethanol. Each formulation was then loaded into an MDI with a target dose delivery of 167 micrograms per action, and tested to determine the mean dose uniformity (ADDU) and the standard deviation of ADDU (generally following the guidelines described in USP601 - Inhalation and Nasal Drug Products: Aerosol, Spray, and Powder Performance Testing). The results of this test are reported in Table Ex1 below.

[0113] [Table 3]

[0114] As can be seen from the test results reported in Table Ex1 above, the applicants unexpectedly found that the use of a carrier containing approximately 85% by weight of HFO-1234ze(E) and 15% ethanol resulted in a standard deviation of the results at levels of less than 20%, which is a dramatic improvement compared to the 45% levels of Examples ExC1A and ExC1B. Furthermore, this unexpected result is achieved while producing an ADDU value that is within 2% of the preferred value of 75%.

[0115] Example 2: Delivery dose of salbutamol sulfate suspension in 85% HFO-1234ze(E) and 15% ethanol and oleic acid Salbutamol sulfate (API) was suspended in a mixture of approximately 85% by weight of HFO-1234ze(E) and 15% by weight of ethanol, along with 0.01% by weight, 0.05% by weight, and 0.1% by weight of oleic acid. The formulation was then loaded into an MDI with a target dose delivery of 167 micrograms per action, and then tested to determine the mean dose uniformity (ADDU) and the standard deviation of ADDU (generally following the guidelines described in USP601 - Inhalation and Nasal Drug Products: Aerosol, Spray, and Powder Performance Testing). The results of this test, along with the results from Comparative Example 1 and Example 1, are reported in Table Ex2 below and shown in Figures Ex2A and Ex2B herein.

[0116] [Table 4]

[0117] As can be seen from the data above and the charts in Figures 2A and 2B, the addition of 0.01 wt% oleic acid to a formulation containing 5 wt% ethanol unexpectedly resulted in a decrease in ADDU, reducing it from 80 to 73.8. On the other hand, it was unexpectedly found that increasing the oleic acid to 0.05% substantially increased the ADDU to a target percentage close to 90% and even beyond 95% for an oleic acid concentration of 0.1 wt%. However, it can also be seen that the standard deviation of the data increases as the amount of oleic acid increases to 0.1 wt% (see Figure 2B). Therefore, for a 5% ethanol formulation, the applicants found that the ability to achieve an ADDU of 75% or more while achieving a standard deviation of less than 15% requires an oleic acid concentration greater than 0% but less than 0.1 wt%, and more preferably about 0.01 wt% to less than 0.1 wt%. These results are unexpected.

[0118] Regarding formulations using 15% ethanol, the data from this example also shows that increasing the oleic acid concentration in the 15% ethanol formulation to above 0.05% by weight results in a decrease in ADDU, reducing it from 87.9% to 73.9%. This result is unexpected.

[0119] Comparative Example 2: Delivery dose of salbutamol sulfate suspension in approximately 100% HFO-1234ze(E) containing oleic acid Comparative Example 1A was repeated, except that salbutamol sulfate (API) was suspended in HFC-1234ze(E) to which 0.01, 0.05, and 0.1% by weight of oleic acid were added, as shown in Table C2 below. Each formulation was then loaded into an MDI with a target dose delivery of 167 micrograms per action, and then tested to determine the mean dose uniformity (ADDU) and the standard deviation of ADDU (generally following the guidelines described in USP601 - Inhalation and Nasal Drug Products: Aerosol, Spray, and Powder Performance Testing). The results of this test, along with the results of Example C1A, are reported in Table ExC2.

[0120] [Table 5]

[0121] As can be seen from the test results reported in Table ExC2 above, the use of a carrier containing approximately 100% HFO-1234ze(E) and amounts of 0.05, 0.01, and 0.1% by weight of oleic acid in each case substantially reduces the ADDU of the formulation to less than 75%.

[0122] Comparative Example 3: Stability of low-dose salbutamol sulfate suspension in approximately 100% HFO-1234ze(E) and HFC-134a The formulation of Comparative Example 1A, along with a formulation prepared using a carrier consisting of HFC-134a, is tested for stability using the Turbiscan Stability Index (TSI), except that the concentration of the API is changed to 0.16% by weight. The TSI is a test known to those skilled in the art, determined as the cumulative sum of the changes in light transmittance or backscatter over the entire sample of the API-containing formulation over a series of time periods after the formulation has been formed into a suspension, such as after shaking the MDI containing the sample. In this test, a higher value indicates a larger change from the baseline (T=0) and higher instability. A lower TSI value indicates a more stable suspension. The TSI is determined according to the following calculation.

[0123]

number

[0124] The test was performed by adding salbutamol sulfate to a clean glass vial at the indicated concentration. If necessary, the indicated amount of ethanol was then weighed into the same vial and sealed with a crimp valve. HFO-1234ze(E) was then pressurized through the valve to a final weight of 10 g. The vial was shaken vigorously for 10 seconds and then loaded into a Turbiscan Lab instrument (Formulaction, France). The sample was scanned at all heights every 25 seconds for 5 minutes at 25°C. TSI was calculated from the bottom of the vial to the meniscus of each formulation. The mean value was calculated from sample heights of 8–14 mm. Peak thickness was measured from the bottom of the sample up to 3 mm, and the absolute ΔBS threshold was 6%. The results of this test are shown in Figure ExC3.

[0125] As the data obtained from this test shows, the use of a carrier consisting of HFO-1234ze produces a more unstable solution at 270 seconds and 300 seconds compared to a carrier consisting of HFC-134a.

[0126] Example 3: Stability of low-dose salbutamol sulfate suspensions in HFO-1234ze(E) and containing 5% and 10% ethanol. Comparative Example 3 was repeated using the same low dose of salbutamol (i.e., 0.16% by weight), except that a carrier blend consisting of (1) approximately 95% by weight of HFO-1234ze(E) and 5% by weight of ethanol (Ex3A) and (2) approximately 90% by weight of HFO-1234ze(E) and 10% by weight of ethanol (Ex3B) was used. The results of this test, along with the results from Comparative Example C3A, are provided in Table Ex3 below and shown in Figure Ex3.

[0127] [Table 6]

[0128] As can be seen from the test results reported in Table Ex3 and the chart in Figure Ex3, the addition of 5% and 10% ethanol improved the stability of the formulations at approximately 75 seconds or more compared to the HFO-1234ze(E) carrier, but these formulations were less stable than 100% HFO-1234ze(E) at less than 75 seconds. Importantly, and unexpectedly, the applicants further found that the formulations consisting of 10% ethanol and 90% HFO-1234ze(E) exhibited superior stability to the 5% ethanol formulation at all time points tested, with this advantage being most pronounced at 30 seconds. This is an important finding because the 30-second stability result is often considered highly relevant, as it generally corresponds to the time the user will use the product and the MDI after shaking.

[0129] Example 4: Stability of high-dose salbutamol sulfate suspensions in HFO-1234ze(E) and containing 5% and 10% ethanol. Repeat Example 3, except that a high dose of salbutamol (i.e., 0.3% by weight) is used, as shown in Table Ex4 below and in the chart in Figure Ex4A, and that an additional concentration of ethanol is used in a carrier consisting of HFO-1234ze(E) and ethanol.

[0130] [Table 7]

[0131] As can be seen from the test results reported in Table Ex4 and the chart in Figure Ex4, the use of a carrier containing 2% ethanol actually results in a dramatic decrease in stability over the entire tested time range compared to 1234ze(E) alone. Unexpectedly, however, increasing the ethanol concentration to 3.5% and 5% results in almost the same dramatic increase in stability over the entire tested time range compared to 1234ze(E) alone and a carrier containing 2.5% ethanol. This unexpected benefit continues for 10% and 15% ethanol as well.

[0132] Furthermore, the applicants have come to understand that the average TSI measured at the center of the sample and the peak width measured at the bottom of the sample can provide insights into particle size change and migration velocity, respectively. In particular, measuring the average ΔBS value passing through the center of each sample provides insights into the size variation behavior (e.g., aggregation) of the formulation. Salbutamol particles suspended in HFO-1234ze(E) showed more rapid and larger size variation than those in HFA-134a. Increasing the amount of ethanol added reduced aggregation in HFO-1234ze(E), and although not bound by any operating theory, this effect is thought to be due to the disruption of the hydrophilic interactions of salbutamol and the reduction of the binding force between suspended particles. This data is shown in the chart in Figure Ex4B.

[0133] Furthermore, the peak thickness of the change in backscatter at the bottom of each sample was measured over the test period, and the migration velocity was calculated by calculating the slope of the linear portion. These results are shown in the chart in Figure 4C.

[0134] The HFO-1234ze suspension (right-hand bar in Figure 4C) exhibited lower migration velocities at 0% and 5% ethanol concentrations compared to the corresponding HFA-134a formulation. However, at 10% ethanol, the migration velocities in HFO-1234ze exceeded those of HFA-134a. This data suggests that there are limits to the effectiveness of ethanol in reducing migration velocities, and a trade-off with performance must be considered.

[0135] Example 5: Stability of high-dose salbutamol sulfate suspension containing 15% ethanol and oleic acid in HFO-1234ze(E). Example 4 was repeated using 15% ethanol and a high dose of salbutamol (i.e., 0.3% by weight), except for the addition of oleic acid concentration, as shown in Table Ex5 below and the chart in Figure Ex5.

[0136] [Table 8]

[0137] As can be seen from the test results reported in Table Ex5 and the chart above, the use of a carrier containing HFO-1234ze(E) and 15% ethanol, but without oleic acid, is unexpectedly more stable over the entire tested time range than the use of 0.01% by weight oleic acid. However, increasing the oleic acid concentration to 0.05% by weight or higher unexpectedly improves stability over the entire tested time range.

Claims

1. A pharmaceutical composition, a. Active pharmaceutical ingredients (APIs) containing salbutamol, b. Approximately 85% to 99% by weight of HFO-1234ze(E), c. Ethanol in an amount of 1% to approximately 15% by weight, d. A pharmaceutical composition comprising more than 0.01% by weight and less than 0.1% by weight of oleic acid.

2. The pharmaceutical composition according to claim 1, comprising more than 0.01% by weight to 0.05% by weight of oleic acid.

3. a. Approximately 85% to 96.5% by weight of HFO-1234ze(E), b. The pharmaceutical composition according to claim 1, comprising 3.5% to about 15% by weight of ethanol.

4. The pharmaceutical composition according to claim 1, comprising more than 0.01% by weight to 0.05% by weight of oleic acid.

5. a. Approximately 85% to 90% by weight of HFO-1234ze(E), b. The pharmaceutical composition according to claim 1, comprising 10% to about 15% by weight of ethanol.

6. The pharmaceutical composition according to claim 1, wherein the active pharmaceutical ingredient (API) is essentially salbutamol.

7. A pharmaceutical composition, a. Active pharmaceutical ingredients (APIs) containing salbutamol, b. Approximately 85% by weight of HFO-1234ze(E), c. Approximately 15% by weight of ethanol, d. A pharmaceutical composition comprising oleic acid in an amount of more than 0.01% by weight to about 0.05% by weight.

8. The pharmaceutical composition according to claim 7, further comprising more than 0.001% by weight and less than about 0.1% by weight of oleic acid.

9. A method for forming a pharmaceutical composition having improved stability, comprising: forming a carrier containing 99% by weight or less of HFO-1234ze and more than 2.5% by weight to less than 10% by weight of ethanol; and suspending an API containing salbutamol in the carrier, wherein the suspension has an improved migration rate compared to a carrier containing more than 10% of ethanol.

10. The method according to claim 9, wherein the step of forming the carrier further comprises forming a carrier containing 0.25% to about 0.5% by weight of salbutamol, and the suspension has an improved TSI compared to a carrier containing 2.5% by weight or less of ethanol.

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