TW202525298A - An inhalable pharmaceutical preparation, device and use thereof - Google Patents

Abstract

The present invention provides an inhalable pharmaceutical formulation, as well as a device and use thereof. The inhalable pharmaceutical formulation can effectively deliver two or more pharmaceutical active ingredients simultaneously and can be used in conjunction with a propellant having low ozone depletion.

Description

An inhalation pharmaceutical preparation, device and use thereof

The present invention relates to an inhalable pharmaceutical formulation, and a device and use thereof. Specifically, the present invention relates to an inhalable pharmaceutical formulation for delivering at least two pharmaceutically active ingredients, and a device and use thereof.

With the health and environmental challenges brought about by urbanization and globalization, respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) have gradually become important conditions that all of humanity must actively address. Studies have shown that the prevalence of asthma has increased since the outbreak of the novel coronavirus disease 2019 (COVID-19). This is caused by the pathophysiological damage to the respiratory tract caused by viral infection, particularly to the upper respiratory tract and bronchi. Studies have also shown that the risk of death among patients with COPD is 3.8 times higher than among those without COPD.

Because asthma, COPD, and COVID-19 all manifest as lung damage, a treatment approach that delivers active pharmaceutical ingredients directly to the site of action is ideal. The optimal approach is to use inhaled medications to improve, control, and reduce epithelial damage and/or enhance T cell responses to achieve treatment for asthma and COPD, while also potentially modulating the COVID-19 pandemic. In this context, the choice of inhaler system will influence the development direction of the drug formulation. Common inhalers include nasal sprays (NS), dry powder inhalers (DPI), soft mist inhalers (SMI), and metered dose inhalers (MDI).

Among them, metered-dose inhalers are active delivery devices that use a propellant to generate pressure. The propellant is a compressed gas that contains a mixed drug and solvent. When released from a pressure canister, it forms an aerosolized drug mist that enters the respiratory tract. Propellants are often chlorofluorocarbons (CFCs), such as chlorofluorocarbons (CFCs), because they have low toxicity and ideal vapor pressure, making them suitable for preparing stable medications. However, traditional CFC propellants are considered to have negative impacts on the environment, so more environmentally friendly propellants have been developed as alternatives, such as perfluorinated compounds (PFCs) and hydrofluoroalkanes (HFAs).

Today's metered-dose inhaler products have completely eliminated the use of CFCs, instead using hydrofluorocarbons (HFAs) as their primary propellants to reduce ozone depletion, such as HFA227ea or HFA134a. However, governments and international organizations continue to seek more environmentally friendly propellants to further reduce the potential ozone depletion caused by these products. Therefore, inhaler product combinations containing novel, low-ozone-depleting propellants are still desired.

Patent Document 1 describes a combination formulation for respiratory diseases containing formoterol and budesonide. This formulation contains the propellant HFA 277, as well as specific content ranges of PEG-1000 and PVP K25. Patent Document 2 describes a pharmaceutical aerosol formulation containing a fluoroolefin with a specific structure as a propellant, thereby reducing the ozone depletion effect of the propellant contained in the pharmaceutical. Patent Document 3 also describes a formulation for respiratory diseases, which contains co-suspended active ingredient particles and a suspended particle carrier, thereby improving the performance of the aerosol particles and avoiding combination effects between the active ingredients. [Prior Art Document] [Patent Document]

[Patent Document 1] U.S. Patent No. 7,759,328B2 [Patent Document 2] U.S. Patent Gazette No. US2006/0269484A1 [Patent Document 3] U.S. Patent No. 9,415,009B2

[Non-patent document 1] Kumar, Raj, et al. "Nanotechnology-assisted metered-dose inhalers (MDIs) for high-performance pulmonary drug delivery applications." Pharmaceutical research 39.11 (2022): 2831-2855.

[Identify the problem to be solved]

The present invention provides an inhalable pharmaceutical formulation, as well as a device and use thereof. The inhalable pharmaceutical formulation can effectively deliver two or more active pharmaceutical ingredients simultaneously and can be used in conjunction with a low-ozone-depleting propellant. [Technical Means]

The present invention provides an inhalable pharmaceutical formulation characterized by comprising: a propellant; at least two active pharmaceutical ingredients; a co-solvent; and an anti-agglomerant; wherein the propellant is tetrafluoropropylene.

The present invention provides an inhalable pharmaceutical formulation characterized by comprising: a propellant; at least two active pharmaceutical ingredients; a co-solvent selected from ethanol or anhydrous ethanol; and an anti-agglomerant; wherein the propellant is tetrafluoropropylene.

In some embodiments, the present invention provides an inhalable pharmaceutical formulation comprising: a propellant; two active pharmaceutical ingredients, wherein the active pharmaceutical ingredients form a suspension or solution with the propellant; a co-solvent selected from ethanol or anhydrous ethanol; and an anti-agglomerant.

In some embodiments, the present invention provides an inhalable pharmaceutical formulation comprising: a propellant; two active pharmaceutical ingredients, one of which forms a suspension with the propellant and the other forms a solution with the propellant; a co-solvent selected from ethanol or anhydrous ethanol; and an anti-agglomerant.

In some embodiments, the propellant is tetrafluoropropylene.

In some embodiments, the co-solvent is anhydrous ethanol, and the anti-aggregating agent is polyethylene glycol (PEG).

In some embodiments, the active pharmaceutical ingredient can be selected from a combination of any two of corticosteroids, beta-2 adrenergic agonists, and anticholinergics.

In some embodiments, the two active pharmaceutical ingredients are a combination of a corticosteroid and a short-acting Beta-2 adrenergic agonist (SABA).

In some embodiments, the concentration of both active pharmaceutical ingredients is less than 0.3% w/w (weight percentage).

In some embodiments, the content of the co-solvent in the formulation is about 12% w/w (weight percentage); the content of the anti-agglomerating agent in the formulation is about 0.5% w/w (weight percentage).

In some embodiments, the content of the co-solvent in the formulation is less than or about 12% w/w (weight percentage); the content of the anti-agglomerating agent in the formulation is less than 0.5% w/w (weight percentage).

In some embodiments, the content of the co-solvent in the formulation is less than or about 10% w/w (weight percentage); the content of the anti-agglomerating agent in the formulation is about 0.1% w/w (weight percentage) to 0.5% w/w (weight percentage).

In some embodiments, the content of the co-solvent in the formulation is less than or about 10% w/w (weight percentage); the content of the anti-agglomerating agent in the formulation is about 0.1% (w/w) to about 0.48% (w/w).

In some embodiments, the content of the co-solvent in the formulation is less than or about 10% w/w (weight percentage); the content of the anti-agglomerating agent in the formulation is about 0.1% (w/w) to about 0.45% (w/w).

In some embodiments, the corticosteroid is budesonide and the EDTA synergist is salbutamol sulfate.

In some embodiments, the corticosteroid is budesonide, and its content in the formulation is 0.136% w/w (weight percentage) to 0.147% w/w (weight percentage).

In some embodiments, the short-acting ethylenediamine synergist is salbutamol sulfate, and its content in the formulation is 0.185% w/w (weight percentage) to 0.200% w/w (weight percentage).

The present invention provides an inhalation device characterized in that the device comprises: an actuator; an aerosol canister for containing an inhalation pharmaceutical formulation; the inhalation pharmaceutical formulation comprising: a propellant; two active pharmaceutical ingredients; a co-solvent selected from ethanol or anhydrous ethanol; and an anti-agglomerant.

The present invention is an inhalation device characterized by comprising: an actuator; and an aerosol canister for loading an inhalable pharmaceutical formulation; wherein the actuator comprises a housing and a nozzle block with a metered dispensing valve; one end of the housing is open to accommodate the aerosol canister, and the other end is open to form an airflow-permeable chamber for introducing the inhalable pharmaceutical formulation into the patient's oral and/or nasal cavity; the nozzle block has an orifice channel that communicates with the metered dispensing valve and is used to guide the inhalable pharmaceutical formulation from the metered dispensing valve into the chamber.

The present invention also provides an inhalation device, characterized in that the device comprises: an actuator; and an aerosol canister for loading an inhalable pharmaceutical preparation; wherein the actuator comprises a housing and a nozzle block with a metered dispensing valve; one end of the housing is open to accommodate the aerosol canister, and the other end is open to form an airflow-permeable chamber for introducing the inhalable pharmaceutical preparation into the patient's oral and/or nasal cavity; the nozzle block has an orifice channel, which is connected to the metered dispensing valve and is used to guide the inhalable pharmaceutical preparation from the metered dispensing valve into the chamber; wherein the inhalable pharmaceutical preparation comprises: a propellant; and at least two active pharmaceutical ingredients; A co-solvent selected from ethanol or anhydrous ethanol; and an anti-agglomerating agent; the propellant is tetrafluoropropylene.

The present invention provides a use of the above-mentioned inhalable pharmaceutical preparation for preparing a drug for treating lung diseases.

The present invention also provides a use of the above-mentioned inhaled pharmaceutical preparation for preparing a medicament for treating a lung disease, wherein the lung disease is asthma or chronic obstructive pulmonary disease. [Effects of the Invention]

The inhalable pharmaceutical preparation of the present invention has a good drug particle dispersion effect. In addition to preventing drug particle aggregation and adhesion to the container, it also allows the drug to be effectively delivered to the lungs through breathing. The inhalable pharmaceutical preparation of the present invention significantly shows essentially no size growth or crystal morphological changes of the active drug ingredient particles over a long period of time. Therefore, the drug particles can be easily redispersed, and there is no problem of hindering the reproducibility of the drug delivery dose during redispersion. The inhalable pharmaceutical preparation of the present invention can maintain good drug uniformity during use and can still maintain a uniform spray dose when spraying multiple doses. It also has good storage stability and meets the requirements of pharmaceutical regulations.

The following discloses the implementation of the present invention. The present invention is not limited to the aspects that completely include the following description. The following description is used to explain the detailed content and implementation effects of the present invention.

The definitions of terms used in this invention are based on currently accepted definitions in the field of pharmaceutical technology and apply throughout this specification, unless otherwise specified in this specification based on specific circumstances.

The inhalable pharmaceutical formulation of the present invention comprises a co-solvent selected from ethanol or anhydrous ethanol. Anhydrous ethanol is preferred. The co-solvent content in the formulation of the present invention is less than 12% w/w (weight percentage); preferably, it is about 1.0% w/w (weight percentage) to 12% w/w (weight percentage); more preferably, it is about 3.0% w/w (weight percentage) to 11% w/w (weight percentage); more preferably, it is about 5.0% w/w (weight percentage) to 10% w/w (weight percentage); and most preferably, it is about 10% w/w (weight percentage) of anhydrous ethanol. Within this concentration range, the suspension formulation is not disrupted, transforming it into a solution, and allows the user to produce a better dispersed and more stable suspension by shaking the inhalation device. It is generally accepted that the use of large amounts of ethanol may cause the particle size in the aerosol formulation to increase, preventing acceptable penetration into the fine bronchial passages of the lungs. However, even with the use of ethanol in the formulation of the present invention, the mass median aerodynamic diameter (MMAD) of the aerosol formulation does not significantly change, or even decreases, when both an anti-agglomerant (polyethylene glycol) and ethanol are included. Furthermore, compared to currently available single-ingredient products, the formulation of the present invention can significantly reduce the chance of drug particles settling in the user's throat while maintaining, slightly increasing, or decreasing the MMAD, thereby improving drug delivery to the area requiring treatment. Furthermore, the formulation of the present invention has been found to be exceptionally effective in redispersing the drug, a benefit not anticipated by the present invention.

Those skilled in the art understand that, in suspensions, the smaller the drug particles, the higher the surface area to volume ratio of the particles, the more likely they are to become thermodynamically unstable, providing a significantly higher surface free energy, which in turn causes the particles to agglomerate. It is generally accepted that particle agglomeration and the adhesion of such particles to the inhaler walls can cause the particles to exit the inhaler in the form of large, stable agglomerates, or prevent the particles from exiting the inhaler and remain adhered to the interior of the inhaler, or even cause the inhaler to become clogged or blocked. Therefore, if drug particles are not controlled and aggregation occurs, the valve of the inhaler device may become clogged, resulting in inaccurate dispensing by the dispensing device, or more seriously, causing the inhaler device to malfunction. Furthermore, drug particle aggregation can cause the suspension to rapidly emulsify or settle. The resulting phase separation may not resolve even with vigorous agitation, making the patient's condition difficult to manage therapeutically. The present inventors have discovered that this cohesive force can be overcome by adding an anti-agglomerant or surfactant. Polyethylene glycol (PEG) can be used as the anti-agglomerant or surfactant, but polyvinylpyrrolidone (PVP) is not used. The inventors discovered that the use of PVP actually enlarges the drug particles, causing them to agglomerate, thereby reducing drug delivery.

Polyethylene glycol refers to non-ionic polyethylene oxide oligomers with varying molecular weights (MW). As a polymer, its molecular weight does not have a fixed value, but rather exists within a certain range. It is generally believed that the molecular weight of PEG ranges from 200 g/mol to 10,000,000 g/mol, and physical properties such as solubility, surface tension, viscosity, freezing point, and melting point vary depending on the molecular weight range. For example, in terms of physical appearance, it can be clearly distinguished as a transparent, non-volatile liquid at room temperature (low molecular weight PEG 200 to PEG 800), a waxy solid (medium molecular weight PEG 1000 to PEG 2000), or a solid (or flakes or powders of high molecular weight PEG 3000 and above). The inventors have discovered that using a liquid polyethylene glycol at room temperature in the pharmaceutical formulation of the present invention significantly reduces drug delivery compared to using a solid polyethylene glycol at room temperature (e.g., PEG 1000). This significantly reduces the actual drug delivery amount, resulting in a dose far below the labeled dose, significantly impacting the therapeutic effect. Furthermore, higher molecular weight PEG (e.g., greater than PEG 3000) indicates a higher number of electron-rich oxygen atoms in the polymer. This leads to a highly cohesive solid formed by hydrogen bonds, making it more difficult to handle and time-consuming to meter during preparation. The present invention has discovered that, when used with a co-solvent, even low molecular weight polyethylene glycol can significantly increase drug delivery, allowing users to achieve therapeutic effects equivalent to the labeled dose. In some embodiments of the present invention, polyethylene glycol with a molecular weight range of 100 to 2400 (PEG100 to PEG2400) can be used; preferably, polyethylene glycol with a molecular weight range of 400 to 2000 (PEG400 to PEG2000); and most preferably, polyethylene glycol with a molecular weight range of 400 to 1000 (PEG400 to PEG1000).

In some embodiments, the use of an anti-agglomerant or surfactant not only significantly prevents particle aggregation within the suspension and adhesion to the container walls, but also significantly reduces the percentage of sedimentation in the throat for solutions. However, the inventors have discovered that using excessive amounts of anti-agglomerant can have a counter-effect, resulting in a decrease in drug delivery as the anti-agglomerant content increases. In the present invention, PEG is used in an amount of less than or about 0.5% w/w (weight percentage), or can be about 0.05% w/w (weight percentage) to about 0.48% w/w (weight percentage), preferably about 0.1% w/w (weight percentage) to about 0.45% w/w (weight percentage), more preferably about 0.1% w/w (weight percentage) to about 0.35% w/w (weight percentage); more preferably about 0.1% w/w (weight percentage) to about 0.3% w/w (weight percentage); most preferably about 0.1% w/w (weight percentage).

The formulations, devices, methods, systems, or combinations thereof of the present invention contain at least one pharmaceutically acceptable propellant. The propellant is selected from a material that has no significant negative impact on ozone and is substantially pharmaceutically harmless. Preferably, the propellant comprises at least one fluorocarbon. In some aspects, the formulations, devices, methods, systems, or combinations thereof of the present invention contain a propellant in a pharmaceutical formulation at a concentration greater than about 80% w/w (weight percentage), preferably greater than 85% w/w (weight percentage).

Compared to some commonly used chlorofluorocarbons (CFCs), the formulations, devices, methods, systems, or combinations thereof of the present invention, despite containing propellants, cause very low or negligible ozone depletion, offering the advantage of essentially no ozone depletion. Compared to many commonly used hydrofluoroalkane compositions, the pharmaceutical formulations, devices, methods, systems, or combinations thereof of the present invention, despite containing propellants, have essentially no global warming contribution.

In some embodiments, the propellant of the present invention comprises at least one fluoroolefin, preferably a hydrofluoroolefin containing 3 to 4 carbon atoms. It is preferably one containing at least one hydrogen atom and free of chlorine, and more preferably tetrafluoropropene. The propellant may be one or more tetrafluoropropenes, or may consist essentially of one or more tetrafluoropropenes. In the present invention, the tetrafluoropropene may be represented by "HFO-1234" to refer to all types of tetrafluoropropenes. In the present invention, the preferred tetrafluoropropene may be selected from: 1,1,1,3-tetrafluoropropene (also known as HFO-1234ze), 2,3,3,3-tetrafluoropropene (also known as HFO-1234yf), or mixtures thereof. When "cis-" and "trans-" precede HFO-1234, the present invention describes the cis- and trans- forms of 1,1,1,3-tetrafluoropropene, or the cis- and trans- forms of 2,3,3,3-tetrafluoropropene, respectively. Although there are certain physical and chemical differences between the cis- and trans-forms of tetrafluoropropene, each of these fluorocarbons is expected to be suitable for use, alone or in combination, in the pharmaceutical formulations, devices, methods, systems, or combinations thereof of the present invention.

In some embodiments, in addition to the preferred fluoroolefins, the pharmaceutical formulations of the present invention may further comprise one or more other hydrofluoroolefins, hydrofluoroalkanes, perfluorocarbons, fluorocarbons, hydrocarbons, alcohols, ethers, or mixtures thereof, provided that the pharmaceutical formulations do not affect the therapeutic efficacy and stability of the present invention, or that their use does not violate laws and environmental regulations. However, the pharmaceutical formulations may comprise no more than 1% w/w (weight percentage), preferably no more than 0.5% w/w (weight percentage), and more preferably no more than 0.1% w/w (weight percentage) of the total pharmaceutical formulation. In the present invention, the preferred propellant is essentially HFO-1234ze, or a composition consisting essentially of HFO-1234ze.

In some embodiments, the present invention provides a pharmaceutical formulation, preferably a pharmaceutical formulation capable of forming a drug aerosol, which, when combined with a device, can form a system or combination for delivery to a specific site within the body of a subject requiring treatment, or for achieving a therapeutic effect by delivery to a preferred site within the body of a subject requiring treatment. The subject requiring treatment can be a human or other mammal. The device can be a metered-dose inhaler, nasal sprayer, or nebulizer, preferably a metered-dose inhaler.

The pharmaceutical formulation of the present invention is suitable for oral, nasal, and/or other mucosal delivery. Preferably, the inhaled pharmaceutical formulation of the present invention is delivered orally to treat pulmonary diseases. The present invention can be combined with a metered-dose inhaler to form a system or combination to meet the needs of treating asthma, COPD, or COVID-19.

In some embodiments, the present invention provides an inhalation device for delivering the pharmaceutical formulation of the present invention through breathing. The inhalation device includes an actuator (or mouthpiece) and a container.

The actuator comprises a housing having an opening at one end adapted to receive the container and an opening at the other end to form a chamber through which airflow can pass, for introducing the medication into the patient's oral and/or nasal cavities. The chamber is preferably adapted for use in a mouthpiece or buccal form by the subject requiring treatment. The actuator may also include a nozzle block for receiving the metered dispensing valve described below. The nozzle block has an orifice channel that is communicable with the metered dispensing valve to direct the medication from the metered dispensing valve into the chamber.

The container is used to hold the pharmaceutical preparation of the present invention and has a metered dispensing valve operable between a non-dispensing position and a dispensing position. The metered dispensing valve is engageable with the nozzle block. The container can be made of aluminum, glass, stainless steel, or plastic. Furthermore, the container can have one or more internal coating layers. The container is preferably an aerosol can.

In some embodiments, the inhalation device of the present invention may be further equipped with a counter or dosage display. The inhalation device of the present invention is preferably a metered dose inhaler.

The inhalation device of the present invention is a metered-dose inhaler. Upon activation, pressure changes cause the propellant and the drug to be ejected. The propellant vaporizes, dispersing the drug to produce a sufficiently fine mist (or aerosol). This mist, combined with the user's breathing movements, effectively delivers the drug to the lungs. The physical processes involved in converting a drug solution or suspension into a fine aerosol using a metered-dose inhaler are complex: First, the turbulent flow of the spray fluid is disrupted, characterized by chaotic variations in pressure and velocity, resulting in unstable and transient turbulent behavior. The entire process occurs in three dimensions. Second, the ambient pressure of the propellant decreases, causing flash distillation (or flash evaporation) as its boiling point drops below the ambient temperature. Regardless of the mechanism, the aerosol/mist particles produced by a metered-dose inhaler must be delivered to their target site, the lungs, through respiration. Particle size distribution affects drug distribution in the lungs, which in turn influences drug therapeutic efficacy. Those skilled in the art understand that aerosol particle size can be described by the Mass Median Aerodynamic Diameter (MMAD), and that particle deposition momentum distribution can be measured to determine particle deposition locations in the lungs.

Furthermore, for such formulations to reach the deep lungs by inhalation, the active agent must be in the form of very fine particles, for example, with a mass median aerodynamic diameter (MMAD) of less than 10 μm. Particles with an MMAD greater than 10 μm may impact the laryngeal wall and generally do not reach the lungs. Particles with an MMAD in the range of 2 μm to 5 μm typically deposit in the respiratory bronchioles. Particles with an MMAD in the range of 0.05 μm to 3 μm may deposit in the alveoli or be absorbed into the bloodstream.

In some embodiments, the pharmaceutical formulations, devices, methods, systems, or combinations thereof provided herein are used for topical drug delivery to treat respiratory diseases. In some embodiments, the suspension or solution of the pharmaceutical active ingredient and a propellant of the present invention is controlled by appropriate pressure and propellant to achieve a particle size distribution (MMAD) within a range suitable for pulmonary treatment. The MMAD is preferably within a range of approximately 0.5 μm to 5 μm, more preferably within a range of approximately 1 μm to 4.5 μm, more preferably within a range of approximately 1.2 μm to 4.2 μm, and even more preferably within a range of approximately 1.5 μm to 4.15 μm.

In some embodiments, when the present invention is used to treat lung diseases, the active pharmaceutical ingredient may or may not be in a micronized or particulate form. In some embodiments, the active pharmaceutical ingredient is preferably in a micronized or particulate form. For example, the active pharmaceutical ingredient may be in a micronized or particulate form with a particle size _D90 (90% cumulative particle size distribution) of less than about ₁₀ microns (nm), preferably less than about 5.5 μm, and more preferably within a range _of about 4.0 to 5.3 μm.

The pharmaceutical formulations, devices, methods, systems, or combinations thereof provided herein contain at least two active pharmaceutical ingredients. Those skilled in the art understand that, compared to formulations containing only a single active pharmaceutical ingredient, the inclusion of two or more active pharmaceutical ingredients in the same formulation can lead to unpredictable changes in the particle size distribution characteristics, stability, uniformity of each delivered dose, and the ratio of a single delivered dose due to the addition of different active pharmaceutical ingredients and the use of different propellants. Formulating pharmaceutical compositions containing two or more active pharmaceutical ingredients is more challenging than formulating formulations containing only a single active pharmaceutical ingredient. In addition to considering the interactions between two or more drugs, the need to consider and adjust the delivery uniformity, ratio, and absorption distribution of two or more drugs is a major challenge. The present invention provides a formulation, method, system, device, or combination thereof that can simultaneously deliver two or more drugs. Furthermore, the therapeutically effective dose can be selected to be relatively smaller than the therapeutically effective dose required for delivering either drug individually, further avoiding or reducing potential medical side effects while achieving a faster onset of action or a longer duration of effect.

The pharmaceutical preparations, devices, methods, systems, or combinations thereof provided by the present invention may contain two or more active pharmaceutical ingredients selected from the group consisting of corticosteroids, long-acting Beta-2 adrenergic agonists (LABA), short-acting Beta-2 adrenergic agonists (SABA), long-acting anticholinergics (LAMA), short-acting anticholinergics (SAMA), antiallergics, anti-inflammatories, bronchodilators, bronchoconstrictors, pulmonary surfactants, and steroids. Examples of the active pharmaceutical ingredients include pulmonary lung surfactants, antibiotics, leukotriene inhibitors or antagonists, mast cell inhibitors, or antihistamines. Preferred active pharmaceutical ingredients for use in the present invention are corticosteroids, long-acting Beta-2 adrenergic agonists (LABA), short-acting Beta-2 adrenergic agonists (SABA), long-acting anticholinergics (LAMA), and short-acting anticholinergics (SAMA).

In some embodiments, the present invention provides a device, method, system, or combination thereof for treating lung diseases, comprising an actuator and an aerosol canister filled with an aerosol formulation, wherein the aerosol formulation may be a suspension or a solution. In some embodiments, the aerosol formulation is preferably a suspension. In some embodiments, the aerosol formulation contains two active pharmaceutical ingredients selected from the group consisting of corticosteroids, long-acting beta-2 adrenergic agonists (LABAs), short-acting beta-2 adrenergic agonists (SABAs), long-acting anticholinergics (LAMAs), and short-acting anticholinergics (SAMAs). Preferably, the two active pharmaceutical ingredients are a combination of a corticosteroid and a beta-2 adrenergic agonist (SABA). More preferably, the combination is a corticosteroid and a short-acting beta-2 adrenergic agonist (SABA). In some embodiments, the two active ingredients in the aerosol formulation can be administered simultaneously or separately as a suspension or solution. In some embodiments, one active ingredient is administered as a suspension and the other as a solution.

The active pharmaceutical ingredient of the present invention can be selected from beclomethasone, budesonide, ciclesonide, flunilide, fluticasone, methyl-prednisolone, mometasone, prednisone, triamcinolone, bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levosalbutamol, orciprenaline or metaproterenol, pirbuterol, Pirbuterol, Procaterol, Rimiterol, Salbutamol (albuterol), Terbutaline, Tulobuterol, Reproterol, Ipratropium, Epinephrine, Bambuterol, Clenbuterol, Formoterol, Salmeterol, Carmoterol, Milveterol, Indacaterol, Glycopyrrolate, Dexipirronium, Scopolamine, Tropicamide Tropicamide, Pirenzepine, Dimenhydrinate, Tiotropium, Darotropium, Aclidinium, Trospium, Ipratropium, Atropine, Benzatropin, Oxitropium, Tripedane, Cortisone, Prednisone, Prednisolone, Dexamethasone, Betamethasone, Triamcinolone, or their conformational isomers, esters, salts, solvents, or combinations thereof. Or combinations thereof. Among them, in some embodiments, preferably selected from beclomethasone, budesonide, ciclesonide, fluticasone, mometasone, carbuterol, fenoterol, levosalbutamol, procaterol, salbutamol or albuterol, tulobuterol, ipratropium, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, glycopyrrolate. Glycopyrrolate, tiotropium, aclidinium, or their configurational isomers, esters, salts, solvents, or combinations thereof. In some embodiments, budesonide, salbutamol or albuterol, and anticholinergics, or their configurational isomers, esters, salts, or solvents, or combinations thereof are further preferred. In some embodiments, a combination of budesonide or its configurational isomers (e.g., the 22R-configurational isomer of budesonide), esters, salts, or solvents, and salbutamol or albuterol, or their configurational isomers, esters, salts, or solvents, is even more preferred. In some embodiments, it is further preferred to use a combination of budesonide and salbutamol sulfate or albuterol sulfate.

In some embodiments, the present invention provides pharmaceutical preparations, devices, methods, systems, or combinations thereof for treating asthma or chronic obstructive pulmonary disease (COPD) via an inhalation device, comprising at least one pharmaceutically effective amount of an active ingredient and at least one pharmaceutically acceptable propellant.

In some embodiments, the present invention provides a device, method, system, or combination thereof, comprising a container, such as an aerosol can, containing a pharmaceutical formulation. The pharmaceutical formulation is a suspension or solution and comprises at least two active pharmaceutical ingredients. The active pharmaceutical ingredients are a combination of budesonide, or a conformational isomer thereof (e.g., the 22R-isomer of budesonide), an ester, a salt, or a solvent thereof, and salbutamol or albuterol, or a conformational isomer thereof, an ester, a salt, or a solvent thereof. In some embodiments, the combination of budesonide and salbutamol sulfate or albuterol sulfate is preferred. In some embodiments, the amount of budesonide per puff after each actuation is in the range of about 70 μg to 100 μg, preferably about 80 μg per puff. In some embodiments, the amount of salbutamol or albuterol per puff after each actuation is in the range of about 75 μg to 100 μg, preferably about 90 μg per puff.

In some embodiments, the present invention eliminates the need for particulate carriers and dispersants, such as lactose, chitosan, or phospholipids, and/or further modifies the morphology of the particulate carriers and dispersants to enhance the stability of the compositions of the present invention, such as by increasing porosity or dispersibility. In some embodiments, the present invention eliminates the use of particulate carriers or dispersants to promote effects such as delayed sedimentation or settling of the drug particle suspension. Preferably, the formulations, devices, methods, systems, or combinations thereof, without the use of particulate carriers or dispersants, achieve suspension stability while simultaneously promoting better dispersion of the drug suspension. In some embodiments, the active pharmaceutical ingredient of the present invention is suspended in a fluid medium (including a propellant).

In some embodiments, the present invention provides a formulation, method, system, device, or combination thereof for treating lung diseases, which allows for uniform drug delivery during multi-dose spraying with minimal shaking or agitation. This method maintains excellent drug uniformity during use. The invention discovered that the density of a propellant-containing solution can be adjusted by adding alcohol (ethanol) and an anti-agglomerant, bringing the density of the propellant-containing solution close to that of the drug, thereby achieving rapid dispersion and maintaining suspension. When drug concentrations below about 0.15% w/w (weight percent) are used in the present invention, the drug is more likely to exhibit insufficient delivery. When drug concentrations greater than about 0.15% w/w (weight percent) but less than about 0.25% w/w (weight percent) are used in the formulations of the present invention, it is sometimes found that the drug is more likely to meet the set dose and is more stable in the formulation, and thus may have a tendency to have an increased suspension time. As drug concentration increases, for example, exceeding about 0.5% w/w (weight percent), the drug generally tends to aggregate and accelerate sedimentation, increasing the volume occupied by the drug and causing rapid sedimentation, which is detrimental to uniform drug application. The drug concentration in the formulation of the present invention is preferably less than about 0.3% w/w (weight percentage), more preferably less than about 0.25% w/w (weight percentage), and even more preferably about 0.2% w/w (weight percentage).

In some embodiments, the pharmaceutical preparations, devices, methods, systems, or combinations thereof of the present invention can be used to treat inflammatory or obstructive lung diseases. The lung disease or condition may be selected from mild asthma, moderate asthma, severe asthma, bronchitic asthma, intrinsic (non-allergic) asthma, extrinsic (allergic) asthma, exercise-induced asthma, occupational asthma, asthma caused by bacterial infection, chronic obstructive pulmonary disease (COPD), chronic obstructive lung disease (COLD), chronic obstructive airway disease (COAD), chronic airflow limitation (CAL), and chronic obstructive respiratory disease (COPD). disease (CORD), worsening of airways hyperreactivity due to drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, emphysema, and cystic fibrosis of the lungs.

The terms "pharmaceutically active ingredient," "drug," and "pharmaceutically" are used broadly within their commonly understood meanings to refer to any material or substance that possesses, or is at least believed to possess, therapeutic or healing properties, and can be used to alleviate disease, treat injury or other illness, and/or pain or other symptoms, and/or for diagnostic purposes. This includes, for example, small molecule drugs and large bioactive macromolecules. As used herein, these terms refer to combinations that are, or are at least believed to be, medically effective.

The terms "therapeutically effective amount" and "pharmaceutically effective amount" refer to an amount of a compound that achieves a therapeutic effect by prophylactically inhibiting or preventing the onset of a disease or condition. A therapeutically effective amount can be an amount that alleviates one or more symptoms of a disease or condition to some extent, partially or completely normalizes one or more physiological or biochemical parameters associated with or causing the disease or condition, and/or reduces the likelihood of recurrence of the disease or condition.

The term "about" or "approximately" is used with respect to a given numerical value, such as a given ratio of active pharmaceutical ingredient, value, particle size, particle diameter, particle size distribution characteristics, or delivery dose uniformity, to indicate that the stated numerical value has a deviation within ±10%.

The term "emitted dose" or "ED" refers to the mass of the active pharmaceutical ingredient emitted from a device. Those skilled in the art understand that the ED is obtained and verified using a Dosage Unit Sampling Apparatus (DUSA).

The term "fine particle dose" or "FPD" refers to the total mass of drug particles smaller than a specified aerodynamic diameter (AOD) after release from the device. Unless a specific AOD value is specified, those skilled in the art generally assume it to be 5 μm. In other words, unless a specific MMAD (Medium Size Area) is specified for the FPD, it refers to the FPD percentage for drug particles with an AOD smaller than 5 μm.

The term "fine particle fraction" or "FPF" refers to the total amount of specific MMAD delivered relative to the total dose emitted and is calculated as FPD divided by ED.

The term "MMAD," or median mass aerodynamic diameter, refers to the aerodynamic diameter of aerosol particles. The calculation of MMAD is based on the United States Pharmacopoeia (USP), and the relevant contents of the USP are incorporated herein.

The term "propellant" refers to a pharmacologically inert substance that generates a sufficiently high vapor pressure at normal room temperature to propel the medication from the canister into the patient's mouth when the MDI is actuated, and then through the patient's airways and into the lungs.

The term "respirable" generally refers to particles, aggregates, droplets, etc., of a size that allows them to be inhaled and reach the airways of the lungs.

The term "suspension" refers to a substance that provides a continuous phase within which particles of the active pharmaceutical ingredient may be dispersed to provide a co-suspension formulation. For example, the active pharmaceutical ingredient of the present invention is in the form of particles in a solute and is substantially insoluble in the propellant in an aerosol formulation.

The terms "suspension stability" and "stable suspension" refer to a suspension formulation that maintains the properties of the active agent particles over time. Suspension stability can be measured by the uniformity of the delivered dose.

The term "labeled dose (LD)" refers to the amount of drug delivered per actuation of an inhaler device, or the labeled dose stated on the inhaler packaging.

The term "genomietric standard deviation" (GSD) refers to a measure of particle size dispersion; it is defined as the ratio of the median particle size to the median particle size ± 1 standard deviation (σ). Aerosols with a GSD of 1.22 are considered polydisperse, and most therapeutic aerosols are polydisperse, with GSDs between 2 and 3. [Example]

Materials: Micronized salbutamol sulfate was purchased from Cambrex (Paullo, Milan, Italy), with a 90% volume particle size of 4.5 μm. Micronized budesonide was purchased from Chemo (Saronno, Varese, Italy), with a 90% volume particle size of 4.0 to 5.3 μm. Anhydrous ethanol was purchased from Honeywell (France), and polyethylene glycol 1000 (PEG 1000) was purchased from Nanjing Well Pharmaceutical Co., Ltd. (China). HFO-1234ze was purchased from a Taiwanese supplier. DF316/50 PRE7 metering valves were purchased from Aptar (UK). 14 ml fluorocarbon polymerization (FCP)-coated aluminum cans were purchased from H&T Presspart (UK). Regarding the commercially available single-dose formulations used as comparators, the salbutamol sulfate comparator was Teva Pharmaceutical Industries, Ltd.'s MDI product, PROAIR®, and the budesonide comparator was the MDI product, DUASMA®.

HPLC conditions: The high-performance liquid chromatography (HPLC) system consisted of an Agilent 1260 Infinity II system equipped with a VWD detector (both purchased from Agilent, California, USA). A HIQ sil C18 HS 5 μm, 4.6 mm × 250 mm column (Oligaga Co., Ltd., Taiwan) was used. The UV detection wavelength was 220 nm, which shifted to 240 nm after 8 minutes. The retention time of albuterol sulfate was 4.6 minutes, and that of budesonide was 17.9 minutes and 18.5 minutes, respectively.

Drug Delivery Unit (DDU) Trial

For drug delivery testing, instrument A was used at a flow rate of 28.3 L/min (±5%), in accordance with the United States Pharmacopeia monograph (USP 601). Each sample was drained by consuming three actuations before sampling. After draining, two actuations were collected in a DUSA tube. The actuation chamber and DUSA tube were then rinsed with an appropriate amount of diluent. The rinse mixture was analyzed by HPLC.

Aerodynamic Particle Size Distribution (APSD) Test

APSD testing utilizes a Next Generation Impactor (NGI). This device is a seven-stage, microporous collector (MOC)-based impactor. The instrument operates at a flow rate of 30 L/min (±5%) in accordance with the United States Pharmacopeia monograph (USP 601). Each cup of the impactor is coated with 1% silicone oil in hexane (w/v). After four actuations, the cup is rinsed with an appropriate amount of diluent, and the rinse mixture is analyzed by HPLC.

Example 1: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide and 1% anhydrous ethanol

The steps for preparing a metered-dose inhaler are as follows: First, the required amounts of active pharmaceutical ingredients (particles) of the two drugs and 1% w/w (weight percentage) anhydrous ethanol are weighed and placed in an FCP aluminum canister. The canister is then sealed and crimped using a metering valve. The required amount of HFO-1234ze(E) is then poured through the metering valve into the sealed and crimped FCP aluminum canister. The canister is then ultrasonically shaken for 10 minutes to form a drug mixture. As shown in Table 1, the drug particles in this mixture are suspended in the HFO-1234ze(E).

[Table 1] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 1% w/w (weight percentage) anhydrous ethanol and HFO-1234ze(E) propellant Element Function % weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 1.000% HFO-1234ze(E) Propellant 98.653%

Example 2: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide and 5% w/w (weight percentage) anhydrous ethanol

The steps for preparing a metered-dose inhaler are as follows: First, the required amounts of the two active pharmaceutical particles are weighed and mixed with 1% w/w (weight percentage) anhydrous ethanol to form a mixture. This mixture is then added to an FCP aluminum canister and crimped using a metering valve. The desired amount of HFO-1234ze(E) is then poured through the metering valve into the crimped FCP aluminum canister, followed by ultrasonic vibration for 10 minutes to form a drug mixture. As shown in Table 2, salbutamol sulfate is suspended in the HFO-1234ze(E), while budesonide is completely dissolved in solution.

[Table 2] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 5% w/w (weight percentage) anhydrous ethanol and HFO-1234ze(E) propellant Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 5.000% HFO-1234ze(E) Propellant 94.653%

Example 3: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide and 10% w/w (weight percentage) anhydrous ethanol

The preparation steps of the metered-dose inhaler were the same as those in Example 2. As shown in Table 3, salbutamol sulfate was suspended in HFO-1234ze(E), and budesonide was completely dissolved in solution.

[Table 3] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 10% w/w (weight percentage) anhydrous ethanol and HFO-1234ze(E) propellant Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 10.000% HFO-1234ze(E) Propellant 89.653%

Example 4: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide and 20% w/w (weight percentage) anhydrous ethanol

The preparation steps of the metered-dose inhaler were the same as those in Example 2. As shown in Table 4, salbutamol sulfate was suspended in HFO-1234ze(E), and budesonide was completely dissolved in solution.

[Table 4] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 20% w/w (weight percentage) anhydrous ethanol and HFO-1234ze(E) propellant. Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 20.000% HFO-1234ze(E) Propellant 79.653%

Example 5: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide and 0.5% w/w (weight percentage) PEG-400

The metered-dose inhaler preparation steps are as follows: First, the required amounts of active pharmaceutical ingredients (particles) of the two drugs and 0.5% w/w (weight percentage) anticoagulant are weighed and placed in an FCP aluminum canister. The canister is then sealed and crimped using a metering valve. The required amount of HFO-1234ze(E) is then poured through the metering valve into the sealed and crimped FCP aluminum canister. The canister is then ultrasonically shaken for 10 minutes to form a drug mixture. As shown in Table 5, the drug particles in this mixture are suspended in the HFO-1234ze(E).

[Table 5] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 0.5% w/w (weight percentage) PEG-400 and HFO-1234ze(E) propellant Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% PEG-400 Anti-agglomerants 0.500% HFO-1234ze(E) Propellant 99.153%

Example 6: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide and 0.1% w/w (weight percentage) PEG-1000

The steps for preparing the metered dose inhaler are as described in Example 5. As shown in Table 6, the drug particles in the mixture are suspended in HFO-1234ze(E).

[Table 6] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 0.1% w/w (weight percentage) PEG-1000 and HFO-1234ze(E) propellants Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% PEG-1000 Anti-agglomerants 0.100% HFO-1234ze(E) Propellant 99.553%

Example 7: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide and 0.5% w/w (weight percentage) PEG-1000

The preparation steps of the metered dose inhaler are as described in Example 5. As shown in Table 7, the drug particles in the mixture are suspended in HFO-1234ze(E).

[Table 7] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 0.5% w/w (weight percentage) PEG-1000 and HFO-1234ze(E) propellant Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% PEG-1000 Anti-agglomerants 0.500% HFO-1234ze(E) Propellant 99.153%

Example 8: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide with 1% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) PEG-400

The metered-dose inhaler preparation steps are as follows: First, the required amounts of two active pharmaceutical ingredients (particles) are weighed, mixed with 1% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) anticoagulant, and placed in an FCP aluminum canister. The canister is then sealed and crimped using a metering valve. The required amount of HFO-1234ze(E) is then poured through the metering valve into the sealed and crimped FCP aluminum canister, followed by ultrasonic vibration for 10 minutes to form a drug mixture. As shown in Table 8, the drug particles in this mixture are suspended in the HFO-1234ze(E).

[Table 8] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 1% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) PEG-400, with HFO-1234ze(E) propellant. Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 1.000% PEG-400 Anti-agglomerants 0.100% HFO-1234ze(E) Propellant 99.053%

Example 9: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide with 1% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) PEG-1000

The preparation steps of the metered dose inhaler are as described in Example 8. As shown in Table 9, the drug particles in the mixture are suspended in HFO-1234ze(E).

[Table 9] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 1% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) PEG-1000, with HFO-1234ze(E) propellant. Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 1.000% PEG-1000 Anti-agglomerants 0.100% HFO-1234ze(E) Propellant 99.053%

Example 10: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide with 10% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) PEG-400

Preparation of the metered-dose inhaler: First, the required amounts of the two active pharmaceutical particles are weighed and mixed with 10% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) anticoagulant to form a mixture. This mixture is then added to an FCP aluminum canister, which is then sealed and crimped using a metering valve. The required amount of HFO-1234ze(E) is then poured through the metering valve into the sealed and crimped FCP aluminum canister, which is then subjected to ultrasonic vibration for 10 minutes to form a drug mixture. As shown in [Table 10], salbutamol sulfate is suspended in the HFO-1234ze(E), while budesonide is completely dissolved in solution.

[Table 10] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 10% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) PEG-400, with HFO-1234ze(E) propellant. Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 10.000% PEG-400 Anti-agglomerants 0.100% HFO-1234ze(E) Propellant 89.053%

Example 11: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide with 10% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) PEG-1000

The preparation steps of the metered-dose inhaler were the same as those in Example 10. As shown in Table 11, salbutamol sulfate was suspended in HFO-1234ze(E), and budesonide was completely dissolved in solution.

[Table 11] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 10% w/w (weight percentage) anhydrous ethanol and 0.1% w/w (weight percentage) PEG-1000, with HFO-1234ze(E) propellant. Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 10.000% PEG-1000 Anti-agglomerants 0.100% HFO-1234ze(E) Propellant 89.053%

Example 12: A metered dose inhaler containing two active particles of salbutamol sulfate and budesonide with 2% w/w (weight percentage) anhydrous ethanol and 0.3% w/w (weight percentage) PEG-1000

The preparation steps of the metered dose inhaler were the same as those in Example 8. As shown in Table 12, the drug particles in the mixture were suspended in HFO-1234ze(E).

[Table 12] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 2% w/w (weight percentage) anhydrous ethanol and 0.3% w/w (weight percentage) PEG-1000, with HFO-1234ze(E) propellant. Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 2.000% PEG-1000 Anti-agglomerants 0.300% HFO-1234ze(E) Propellant 97.353%

Example 13: Metered-dose inhaler containing two active particles of salbutamol sulfate and budesonide with 10% w/w (weight percentage) anhydrous ethanol and 0.5% w/w (weight percentage) PEG-1000

The preparation steps of the metered-dose inhaler were the same as those in Example 10. As shown in Table 13, salbutamol sulfate was suspended in HFO-1234ze(E), and budesonide was completely dissolved in solution.

[Table 13] Salbutamol sulfate and budesonide pressurized inhalation suspension containing 10% w/w (weight percentage) anhydrous ethanol and 0.5% w/w (weight percentage) PEG-1000, with HFO-1234ze(E) propellant. Element Function %weight Salbutamol sulfate API 0.200% budesonide API 0.147% Anhydrous ethanol solvent 10.000% PEG-1000 Anti-agglomerants 0.500% HFO-1234ze(E) Propellant 89.153%

The drug delivery performance of pressurized inhalation suspensions of albuterol sulfate and budesonide using different formulations of HFO-1234ze propellant was compared. The drug delivery rates for different examples are shown in Figures 1 through 3 and Table 14. The actual delivered dose is expressed as a percentage of the labeled delivered dose (108 mcg for albuterol sulfate and 80 mcg for budesonide). In accordance with USP 601, the total amount of drug collected from all DUSA devices (residual amount) divided by the total number of actuations per measured discharge should generally be within a range of no less than 85% and no more than 115% of the labeled delivered dose to meet the standard. Therefore, the pharmacopoeia stipulates that the drug delivery dose should not be less than 85% of the labeled dose. Overall test results show that all commercially available control products meet this standard; however, the drug delivery dose in Example 1 (1% w/w anhydrous ethanol) and Examples 5 and 7 (0.5% w/w PEG) formulations falls below the standard requirement. Furthermore, the test revealed that drug delivery was impossible in a formulation containing 0.1% w/w PEG-400 due to severe aggregation. Furthermore, even increasing the concentration to 0.5% w/w still resulted in poor drug delivery. For PEG 1000, increasing the concentration to 0.5% w/w actually decreased drug delivery compared to 0.1% w/w. Therefore, the trial data revealed that drug delivery in formulations using either ethanol or PEG alone varied with the concentration of either ethanol or PEG, as well as the type of PEG used. In contrast, formulations using both ethanol and PEG showed consistently high drug delivery rates exceeding 85% at all concentrations, demonstrating that combined use of both agents resulted in superior drug delivery.

[Table 14] Salbutamol sulfate budesonide Salbutamol sulfate inhaler control (using HFA134a) and budesonide inhaler control (using HFA134a) 101 89 Preparations containing HFO-1234ze 1% anhydrous ethanol 76 65 5% anhydrous ethanol 90 89 10% anhydrous ethanol 103 85 20% anhydrous ethanol 96 92 0.5% PEG400 36 27 0.1% PEG1000 97 95 0.5% PEG1000 84 81 1% anhydrous ethanol and 0.1% PEG-400 98 88 1% anhydrous ethanol and 0.1% PEG-1000 87 87 10% anhydrous ethanol and 0.1% PEG-400 97 88 10% anhydrous ethanol and 0.1% PEG-1000 91 90 2% anhydrous ethanol and 0.3% PEG-1000 90 84 10% anhydrous ethanol and 0.5% PEG-1000 109 85

Table 15 summarizes the aerodynamic particle size distribution (APSD) of albuterol sulfate and budesonide for comparative commercial products and examples of the present invention, including fine particle dose (FPD), fine particle fraction (FPF), mass median aerodynamic diameter (MMAD), and throat settling fraction. Surprisingly, while the formulation using only anhydrous ethanol exhibited good drug delivery unit (DDU) data, budesonide and albuterol sulfate exhibited distinctly different APSD performance. The aggregated data show that, as the amount of anhydrous ethanol used increases, budesonide's FPD and FPF improve compared to the commercially available single-formulation formulation, and the percentage of budesonide deposited in the throat decreases. However, the effect on salbutamol sulfate deteriorates with increasing ethanol use, compared to the commercially available single-formulation formulation. When PEG is used alone, drug delivery (DDU) performance is generally poor; however, when used in combination with anhydrous ethanol, significant improvements are achieved. Whether using high or low concentrations of anhydrous ethanol or PEG of varying molecular weights, superior results are observed in both fine particle size and throat deposition compared to the commercially available single-formulation formulation. When both ethanol and PEG were used in the formulation, the FPD, FPF, and MMAD values were equivalent to or better than the evaluation criteria at various concentration combinations of the two drugs, and the laryngeal deposition rates of both drugs were also lower.

[Table 15] Salbutamol sulfate budesonide FPD, ＜ 5μm FPF, ＜ 5μm MMAD (μm) Throat Deposition(%) FPD, ＜ 5μm FPF, ＜ 5μm MMAD (μm) Throat Deposition(%) Salbutamol sulfate inhaler control (using HFA134a) and budesonide inhaler control (using HFA134a) 60.0 64 2.47 25% 23.2 36 4.20 47% The compound preparation containing HFO-1234ze in the embodiment of the present invention 1% anhydrous ethanol 49.4 73 2.36 15% 21.8 45 3.65 35% 5% anhydrous ethanol 73.1 73 2.24 17% 22.5 34 1.97 44% 10% anhydrous ethanol 52.2 48 2.22 41% 34.2 51 1.54 40% 20% anhydrous ethanol 42.4 43 2.31 45% 29.3 44 1.66 46% 0.5% PEG1000 57.2 64 3.49 16% 36.8 60 3.70 19% 1% anhydrous ethanol and 0.1% PEG-400 76.7 71 2.79 16% 29.5 41 4.20 34% 1% anhydrous ethanol and 0.1% PEG-1000 65.3 73 2.72 14% 25.2 41 4.05 38% 10% anhydrous ethanol and 0.1% PEG-400 72.2 67 2.46 28% 50.5 71 1.72 twenty two% 10% anhydrous ethanol and 0.1% PEG-1000 67.7 67 2.37 twenty four% 41.9 67 1.75 25% 2% anhydrous ethanol and 0.3% PEG-1000 70.5 74 2.82 13% 30.7 50 4.05 25% 10% anhydrous ethanol and 0.5% PEG-1000 68.1 56 3.38 27% 39.0 57 2.62 28%

On the other hand, the results of pressurized inhalation suspensions of albuterol sulfate and budesonide using different formulations of HFO-1234ze as the propellant show that, while the FPD and FPF data for the 0.5% w/w PEG1000 formulation were comparable to those of the commercially available control, the DDU was marginally below the standard. Furthermore, in Example 13, when the PEG dosage was increased to approximately 0.5% w/w, while the FPD and FPF of budesonide continued to improve compared to the commercially available single-ingredient formulation, the FPF of albuterol sulfate was significantly lower than that of the commercially available product.

The present invention provides an inhaled drug formulation and uses a metered dose inhaler (MDI) for treating asthma and other chronic obstructive pulmonary diseases and for delivering the drug to the treatment site. Therefore, the present invention includes a method for preparing a formulation for treating a lung disease in an organism (e.g., a human or animal), comprising administering a composition of the present invention comprising a combination drug and an inhalation device to the organism in need of treatment. Although the present invention has been described and exemplified above in conjunction with certain preferred embodiments, the present invention is not necessarily limited to these examples and embodiments.

without

[Figure 1] The delivered amounts of salbutamol sulfate and budesonide in HFO-1234ze(E) at various concentrations of anhydrous ethanol, according to this embodiment. The amounts are expressed as percentages relative to the target labeled amounts (salbutamol 108 mcg and budesonide 80 mcg). [Figure 2] The delivered amounts of salbutamol sulfate and budesonide in HFO-1234ze(E) at various concentrations of PEG-400 or PEG-1000, according to this embodiment. The amounts are expressed as percentages relative to the target labeled amounts (salbutamol 108 mcg and budesonide 80 mcg). [Figure 3] In this embodiment, the delivered amounts of salbutamol sulfate and budesonide in HFO-1234ze(E) containing different concentrations of anhydrous ethanol and PEG-1000 or PEG-400 are shown as percentages relative to the target labeled amounts (salbutamol 108 mcg and budesonide 80 mcg). [Figure 4] Schematic diagram of an inhalation device of the present invention.

Claims (10)

An inhalable pharmaceutical formulation comprising: a propellant; at least two active pharmaceutical ingredients; a co-solvent selected from ethanol or anhydrous ethanol; and an anti-agglomerant; wherein the propellant is tetrafluoropropylene. The inhalation pharmaceutical preparation as described in claim 1, wherein the co-solvent is anhydrous ethanol and the anti-aggregating agent is polyethylene glycol (PEG). The inhaled pharmaceutical preparation as described in claim 1, wherein the active pharmaceutical ingredient can be selected from a combination of any two of corticosteroids, beta-2 adrenergic agonists, and anticholinergics. The inhalation pharmaceutical formulation of claim 1, wherein the concentration of the two active pharmaceutical ingredients is less than about 0.3% (w/w). The inhalable pharmaceutical formulation of claim 4, wherein the content of the co-solvent in the formulation is less than about 12% (w/w); and the content of the anti-aggregant in the formulation is less than 0.5% (w/w). The inhalable pharmaceutical formulation of claim 5, wherein the content of the co-solvent in the formulation is less than about 10% (w/w); and the content of the anti-aggregant in the formulation is from about 0.1% (w/w) to about 0.45% (w/w). The inhaled pharmaceutical preparation as described in claim 1, wherein the active pharmaceutical ingredient is selected from a corticosteroid and a short-acting EDTA synergist; the corticosteroid is budesonide; the short-acting EDTA synergist is salbutamol sulfate. The inhaled pharmaceutical preparation as described in claim 3, wherein the corticosteroid is budesonide, and the content of the corticosteroid in the preparation is 0.136% to 0.147%; the short-acting ethylenediamine synergist is salbutamol sulfate, and the content of the short-acting ethylenediamine synergist in the preparation is 0.185% to 0.200%. An inhalation device, characterized in that it comprises: an actuator; and an aerosol canister for being filled with the inhalable pharmaceutical formulation described in any one of claims 1 to 8; the actuator comprises a housing and a nozzle block with a metered dispensing valve; the housing has an opening at one end for accommodating the aerosol canister and an opening at the other end for forming an airflow-permeable chamber for introducing the inhalable pharmaceutical formulation into the oral and/or nasal cavity of a patient; the nozzle block has an orifice channel that communicates with the metered dispensing valve and is used to guide the inhalable pharmaceutical formulation from the metered dispensing valve into the chamber. Use of the inhalable pharmaceutical preparation according to any one of claims 1 to 8 for preparing a medicament for treating a lung disease.