Inhalable pharmaceutical preparation, apparatus, and use thereof

Abstract

Provided are an inhalable pharmaceutical preparation, an apparatus using same, and use thereof in treating pulmonary diseases. The inhalable pharmaceutical preparation comprises a propellant, at least two active pharmaceutical ingredients, a cosolvent, and an anti-aggregation agent, wherein the cosolvent is selected from ethanol and absolute ethanol, and the propellant is tetrafluoropropene.

Description

Inhaled pharmaceutical preparations, devices and their uses Technical Field

[0001] This application relates to an inhaled pharmaceutical preparation, and an apparatus and use thereof. Specifically, this application relates to an inhaled pharmaceutical preparation that delivers at least two pharmaceutically active ingredients, and an apparatus and use thereof. Background Technology

[0002] With the rise of urbanization and globalization, health and environmental issues have led to respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) becoming increasingly important health concerns for all of humanity. Studies have shown that the prevalence of asthma has increased since the COVID-19 pandemic, likely due to pathophysiological damage to the respiratory tract caused by viral infection, particularly the upper respiratory tract and bronchi. Furthermore, research indicates that patients with COPD have a 3.8 times higher risk of death than those without COPD.

[0003] Since asthma, COPD, and COVID-19 all involve lung damage, treatments that deliver the active pharmaceutical ingredient directly to the site of action are ideal. The best approach is to use inhaled medications to improve, control, and reduce epithelial damage and / or improve T-cell responses, thereby treating asthma and COPD while simultaneously providing beneficial regulatory effects against the COVID-19 pandemic. In this context, the choice of inhaler system will influence the direction of drug formulation development. Common inhalers include nasal sprays (NS), dry powder inhalers (DPI), soft mist inhalers (SMI), and metered-dose inhalers (MDI).

[0004] In common inhalers, metered-dose inhalers (MDIs) are active delivery devices that utilize propellant pressure. The propellant is a compressed gas; the medication and solvents mixed within it are released from the pressurized container, forming an atomized drug mist that enters the respiratory tract. Propellants are often chlorofluorocarbons (CFCs), which are suitable for formulating stable medications due to their low toxicity and ideal vapor pressure. However, traditional CFC propellants are considered to have negative environmental impacts, therefore more environmentally friendly propellants have been developed as alternatives, such as perfluorinated compounds (PFCs) and hydrofluorocarbons (HFAs).

[0005] Modern metered-dose inhaler (MDI) devices have completely eliminated the use of chlorofluorocarbons (CFCs), replacing them with hydrofluorocarbons (HFCs) as the primary propellant to reduce ozone depletion, such as HFA227ea or HFA134a. However, governments and international organizations still hope to introduce more environmentally friendly propellants to further reduce the potential ozone layer damage caused by these products. Therefore, in the field of inhaler products, there remains a demand for combination formulations that incorporate novel, low-ozone-depleting propellants.

[0006] US Patent 7,759,328B2 discloses a combination formulation for respiratory diseases comprising formoterol and budesonide, containing the propellant HFA 277, and specific amounts of PEG-1000 and PVP K25. US Patent Publication US2006 / 0269484A1 discloses a pharmaceutical aerosol formulation containing a fluoroolefin with a specific structure as a propellant, thereby reducing ozone depletion of the propellant in the drug. US Patent 9,415,009B2 also discloses a formulation for respiratory diseases comprising 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. See also Kumar, Raj, et al. "Nanotechnology-assisted metered-dose inhalers (MDIs) for high-performance pulmonary drug delivery applications." Pharmaceutical research 39.11 (2022): 2831-2855. Summary of the Invention

[0007] The purpose of this application is to provide an inhaled pharmaceutical preparation, as well as an apparatus and uses for using the inhaled pharmaceutical preparation. The inhaled pharmaceutical preparation can effectively deliver two or more active pharmaceutical ingredients simultaneously and can be used in conjunction with a low-ozone-consuming propellant.

[0008] In a first aspect, this application provides an inhaled pharmaceutical formulation comprising: a propellant; at least two pharmaceutically active ingredients; a co-solvent; and an anti-coagulation agent; wherein the propellant is tetrafluoropropylene.

[0009] Secondly, this application provides an inhaled pharmaceutical formulation comprising: a propellant; at least two pharmaceutically active ingredients; a co-solvent selected from ethanol or anhydrous ethanol; and an anticoagulant; wherein the propellant is tetrafluoropropylene.

[0010] In some embodiments, this application provides an inhaled pharmaceutical formulation comprising: a propellant; two pharmaceutically active ingredients, wherein the pharmaceutically active ingredients form a suspension or solution with the propellant; a co-solvent selected from ethanol or anhydrous ethanol; and an anticoagulant.

[0011] In some embodiments, this application provides an inhaled pharmaceutical formulation comprising: a propellant; two pharmaceutically active ingredients, wherein one pharmaceutically active ingredient forms a suspension with the propellant and the other pharmaceutically active ingredient forms a solution with the propellant; a cosolvent selected from ethanol or anhydrous ethanol; and an anticoagulant.

[0012] In some implementations, the propellant is tetrafluoropropylene.

[0013] In some embodiments, the co-solvent is anhydrous ethanol, and the anti-coagulation agent is polyethylene glycol (PEG).

[0014] In some embodiments, the active pharmaceutical ingredient may be selected from any combination of two of the following: corticosteroids, beta-2 adrenergic agonists, and anticholinergics.

[0015] In some embodiments, the two active pharmaceutical ingredients are a combination of a corticosteroid and a short-acting beta-2 adrenergic agonist (SABA).

[0016] In some embodiments, the concentrations of both active pharmaceutical ingredients are less than 0.3% w / w (weight percentage).

[0017] In some embodiments, the co-solvent is present in the formulation at a content of about 12% w / w (weight percentage); the anti-coagulant is present in the formulation at a content of about 0.5% w / w (weight percentage).

[0018] In some embodiments, the co-solvent is present in a concentration of less than or about 12% w / w (weight percentage) in the formulation; and the anticoagulant is present in a concentration of less than 0.5% w / w (weight percentage) in the formulation.

[0019] In some embodiments, the co-solvent is present in a concentration of less than or about 10% w / w in the formulation; and the anticoagulant is present in a concentration of about 0.1% w / w to 0.5% w / w in the formulation.

[0020] In some embodiments, the co-solvent is present in a concentration of less than or about 10% w / w in the formulation; and the anticoagulant is present in a concentration of about 0.1% (w / w) to about 0.48% (w / w) in the formulation.

[0021] In some embodiments, the co-solvent is present in a concentration of less than or about 10% w / w (weight percentage) in the formulation; and the anticoagulant is present in a concentration of about 0.1% (w / w) to about 0.45% (w / w) in the formulation.

[0022] In some embodiments, the corticosteroid drug is budesonide, and the glycoside synergist is salbutamol sulfate.

[0023] In some embodiments, the corticosteroid is budesonide, and its content in the formulation is from 0.136% w / w (weight percentage) to 0.147% w / w (weight percentage).

[0024] In some embodiments, the short-acting ethylenediamine synergist is salbutamol sulfate, and its content in the formulation is from 0.185% w / w (weight percentage) to 0.200% w / w (weight percentage).

[0025] Thirdly, this application provides an inhalation device comprising: an actuator; and an aerosol can for filling an inhaled pharmaceutical preparation; wherein the inhaled pharmaceutical preparation comprises a propellant, two active pharmaceutical ingredients, a cosolvent selected from ethanol or anhydrous ethanol, and an anticoagulant.

[0026] Fourthly, this application provides an inhalation device comprising: an actuator; and an aerosol can for filling an inhaled pharmaceutical preparation; wherein the actuator comprises a housing and a nozzle block with a dispensing valve; one end of the housing is open to receive the aerosol can, and the other end is open to an airflow-through chamber for introducing the inhaled pharmaceutical preparation into the patient's oral cavity and / or nasal cavity; the nozzle block has an orifice channel communicating with the dispensing valve and for guiding the inhaled pharmaceutical preparation from the dispensing valve into the chamber.

[0027] Fifthly, this application also provides an inhalation device comprising:

[0028] Actuator; and

[0029] Aerosol cans are used to fill inhaled pharmaceutical preparations;

[0030] The actuator includes a housing and a nozzle block with a metering valve; one end of the housing is open to accommodate the aerosol can, and the other end is open to a flow-through chamber for introducing the inhaled pharmaceutical preparation into the patient's oral cavity and / or nasal cavity.

[0031] The nozzle block has an orifice channel that communicates with the dispensing valve and is used to guide the inhaled pharmaceutical preparation from the dispensing valve into the chamber;

[0032] The inhaled pharmaceutical preparation comprises: a propellant; at least two active pharmaceutical ingredients; a cosolvent selected from ethanol or anhydrous ethanol; and an anticoagulant.

[0033] In one embodiment, the propellant is tetrafluoropropylene.

[0034] Sixthly, this application provides the use of the above-mentioned inhaled pharmaceutical preparation in the preparation of a drug for the treatment of lung diseases.

[0035] Seventhly, this application provides the use of the above-mentioned inhaled pharmaceutical preparation for the preparation of a medicament for the treatment of lung diseases; wherein the lung disease is asthma or chronic obstructive pulmonary disease.

[0036] In some embodiments, the inhaled pharmaceutical formulation of this application exhibits excellent drug particle dispersion, preventing particle aggregation and adhesion to the container, and enabling effective delivery of the drug to the lungs via inhalation. In some embodiments, the inhaled pharmaceutical formulation of this application shows virtually no increase in the size or change in the crystal morphology of the active pharmaceutical ingredient particles over a relatively long period, thus allowing for easy redispersibility of the drug particles without hindering the reproducibility of the delivered dosage. In some embodiments, the inhaled pharmaceutical formulation of this application maintains good drug uniformity during use, ensuring a consistent dosage even with multiple sprays. In some embodiments, the inhaled pharmaceutical formulation of this application exhibits good storage stability, meeting pharmaceutical regulatory requirements. Attached Figure Description

[0037] Figure 1 shows the delivery doses of salbutamol sulfate and budesonide in one embodiment, with different concentrations of anhydrous ethanol in HFO-1234ze(E). The doses are expressed as a percentage relative to the target labeled amounts (salbutamol 108 mcg and budesonide 80 mcg).

[0038] Figure 2 shows the delivery doses of salbutamol sulfate and budesonide in HFO-1234ze(E) containing different concentrations of PEG-400 or PEG-1000 in one embodiment. The doses are expressed as a percentage relative to the target labeled amounts (salbutamol 108 mcg and budesonide 80 mcg).

[0039] Figure 3 shows the delivery doses of salbutamol sulfate and budesonide in one embodiment, with different concentrations of anhydrous ethanol and PEG-1000 or PEG-400 in HFO-1234ze(E). The doses are expressed as a percentage relative to the target labeled amounts (salbutamol 108 mcg and budesonide 80 mcg).

[0040] Figure 4 shows an exemplary diagram of the inhalation device of this application. Detailed Implementation

[0041] The following further describes the embodiments of this application. This application is not limited to a solution that fully includes the structure described below. The following description is only used to illustrate the details of this application and the effects of its implementation.

[0042] The definitions used in this application are based on the generally accepted definitions in the field of pharmaceutical technology and apply throughout the specification, unless otherwise specified in the specification based on specific circumstances.

[0043] The inhaled pharmaceutical formulation of this application comprises a co-solvent selected from ethanol or anhydrous ethanol. The co-solvent is preferably anhydrous ethanol. The co-solvent content in the formulation of this application is less than 12% w / w (weight percentage); preferably from about 1.0% w / w (weight percentage) to 12% w / w (weight percentage); more preferably from about 3.0% w / w (weight percentage) to 11% w / w (weight percentage); preferably from about 5.0% w / w (weight percentage) to 10% w / w (weight percentage); and most preferably about 10% w / w (weight percentage) of anhydrous ethanol. Within this concentration range, the suspension formulation is not disrupted, preventing it from becoming a solution, and allows the subject to generate a better-dispersed and more stable suspension by shaking the inhalation device. It is generally believed that using large amounts of ethanol may result in larger particle sizes in the aerosol formulation, making it impossible to penetrate the bronchiolar channels of the lungs in an acceptable manner. However, even when ethanol is used in the formulation of this application, the median mass aerodynamic diameter (MMAD) of the aerosol formulation does not change significantly or decrease when both an anticoagulant (polyethylene glycol) and ethanol are included. Furthermore, compared to currently available single-component commercially available products, the formulation of this application can significantly reduce the probability of drug particles settling in the throat of the subject while maintaining, slightly increasing, or decreasing MMAD, thus improving the effectiveness of drug delivery to the site of treatment. Simultaneously, the formulation of this application demonstrates particularly significant redispersibility, an effect that would not have been anticipated by those skilled in the art.

[0044] Those skilled in the art understand that in suspensions, the smaller the drug particles, the higher the surface area to volume ratio, the more prone they are to thermodynamic instability, providing significantly high surface free energy and thus promoting particle aggregation. It is generally believed that particle aggregation and adhesion of such particles to the inhaler wall can cause particles to leave the inhaler as large and stable agglomerates, or prevent them from leaving the inhaler and remain adhered to its interior, even leading to blockage or clogging. Therefore, if drug particle aggregation is not controlled, the valves of the inhalation device may become clogged, resulting in inaccurate dispensing and, more seriously, malfunction of the inhalation device. Furthermore, drug particle aggregation can also cause rapid emulsification or precipitation of the suspension, and the resulting phase separation may not be resolved even with vigorous shaking, making it difficult to control the patient's condition. This application discovers that this cohesive force can be overcome by adding an anti-agglomerate or surfactant, such as polyethylene glycol (PEG), but not polyvinylpyrrolidone (PVP). The inventors discovered that using PVP actually makes drug particles larger and more prone to agglomeration, thus reducing the amount of drug delivered.

[0045] Polyethylene glycol (PEG) refers to nonionic polyethylene oxide oligomers with different molecular weights (MW). As a polymer, its molecular weight does not have a fixed value but rather exists within a range. Generally, the molecular weight of PEG is considered to range from 200 g / mol to 10,000,000 g / mol, and depending on the molecular weight range, various physical properties such as solubility, surface tension, viscosity, freezing point, and melting point vary. For example, physically, it can be clearly distinguished as a transparent, non-volatile liquid at room temperature (low molecular weight PEG200 to PEG800), a waxy solid (medium molecular weight PEG1000 to PEG2000), or a solid (or as flakes or powder, high molecular weight PEG3000 and above). The inventors of this application discovered that when using polyethylene glycol (PEG) that is liquid at room temperature in the same dosage in the pharmaceutical formulation of this application, compared with using PEG that is solid at room temperature (e.g., PEG1000), the drug delivery rate is significantly reduced, resulting in an actual drug delivery dose far lower than the labeled dose, which will greatly affect the therapeutic effect on the subjects. Furthermore, the higher the molecular weight of the PEG used (e.g., higher than PEG3000), the more electron-rich oxygen atoms are present in the polymer. Solids with high cohesiveness due to intermolecular forces such as hydrogen bonds are increasingly difficult to process, making the metering process more time-consuming in the preparation operation. This application found that, when used in conjunction with a co-solvent, even with low molecular weight PEG, the drug delivery rate can be significantly increased, allowing subjects to achieve therapeutic effects equivalent to the labeled dose. In some embodiments of this application, the polyethylene glycol used may have a molecular weight range of 100 to 2400 (PEG100 to PEG2400); preferably, a molecular weight range of 400 to 2000 (PEG400 to PEG2000); and most preferably, a molecular weight range of 400 to 1000 (PEG400 to PEG1000).

[0046] In some embodiments, the use of anticoagulants or surfactants not only has a significant effect on preventing particle aggregation and adhesion to container walls within the suspension, but also significantly reduces the percentage of sedimentation in the throat for drug dosage forms that are solutions. However, the inventors of this application have discovered that using excessive amounts of anticoagulants can, to some extent, have the opposite effect, causing the drug delivery dose to decrease in the opposite direction as the anticoagulant content increases. In this application, the amount of PEG used is less than or about 0.5% w / w (weight percentage), or 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); preferably about 0.1% w / w (weight percentage) to about 0.3% w / w (weight percentage); and most preferably about 0.1% w / w (weight percentage).

[0047] The formulations, apparatus, methods, systems, or combinations thereof of this application contain at least a pharmaceutically acceptable propellant. The propellant is selected from materials that have no significant negative impact on ozone and are substantially pharmaceutically harmless. Preferably, the propellant comprises at least one fluorocarbon. In some embodiments, the propellant used in the formulations, apparatus, methods, systems, or combinations thereof of this application has a content in the pharmaceutical formulation greater than about 80% w / w (weight percentage), preferably greater than 85% w / w (weight percentage).

[0048] Compared to some commonly used chlorofluorocarbons (CFCs), the formulations, apparatus, methods, systems, or combinations thereof of this application, although containing propellants, cause very low or negligible ozone depletion, thus having the advantage of essentially not causing ozone depletion. Compared to many commonly used hydrofluorocarbon compositions, the pharmaceutical formulations, apparatus, methods, systems, or combinations thereof of this application, although containing propellants, substantially do not contribute to global warming.

[0049] In some embodiments, the propellant in this application comprises at least one fluoroolefin, preferably a hydrofluoroolefin containing 3 to 4 carbon atoms. Preferably, the propellant contains at least one hydrogen atom and is chlorine-free, more preferably tetrafluoropropylene. The propellant may be one or more tetrafluoropropylenes, or substantially composed of one or more tetrafluoropropylenes. In this application, the tetrafluoropropylene may be designated as "HFO-1234" to refer to all types of tetrafluoropropylene. In this application, preferred tetrafluoropropylene may be selected from: 1,1,1,3-tetrafluoropropylene (1,1,1,3-Tetrafluoropropene, also known as HFO-1234ze), 2,3,3,3-tetrafluoropropylene (2,3,3,3-Tetrafluoropropene, also known as HFO-1234yf), or mixtures thereof. When prefixed with "cis-" and "cis-", HFO-1234, the cis and trans forms of 1,1,1,3-tetrafluoropropylene, or the cis and trans forms of 2,3,3,3-tetrafluoropropylene, are described in this application, respectively. Although there are certain differences in physical and chemical properties between the cis and trans configurations of tetrafluoropropylene, each of these fluorinated hydrocarbons is expected to be suitable, alone or in combination, for use in the pharmaceutical formulations, apparatuses, methods, systems, or combinations thereof of this application.

[0050] In some embodiments, in addition to the preferred fluoroolefins, the pharmaceutical formulations of this application may further contain one or more other hydrofluoroolefins, hydrofluoroalkanes, perfluorocarbons, fluorocarbons, hydrocarbons, alcohols, ethers, or mixtures thereof, provided that they do not affect the therapeutic effect and stability of this application, or that their use does not violate laws and environmental regulations, provided that their content does not exceed 1% w / w (weight percentage) of the total, preferably not more than 0.5% w / w (weight percentage), and more preferably not more than 0.1% w / w (weight percentage). In this application, the preferred propellant is essentially HFO-1234ze, or a composition essentially composed of HFO-1234ze.

[0051] In some embodiments, this application provides a pharmaceutical preparation, preferably a pharmaceutical preparation capable of forming a drug aerosol, which, when combined with a device, can form a system or combination for use at 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 the subject requiring treatment. The subject requiring treatment can be a human or other mammal. The device can be a metered-dose inhaler, a nasal spray, or a nebulizer, preferably a metered-dose inhaler.

[0052] The pharmaceutical formulations of this application are suitable for delivery via the mouth, nose, and / or other mucous membranes. Preferably, the inhaled pharmaceutical formulations of this application can be delivered orally to treat diseases occurring in the lungs. This application can be used in conjunction with metered-dose inhaler systems or combinations to meet the needs of treating asthma, COPD, or COVID-19.

[0053] In some embodiments, this application provides an inhalation device for delivering the pharmaceutical formulation of this application through breathing. The inhalation device includes an actuator (or mouthpiece) and a container.

[0054] The actuator includes a housing with one end open to fit into the container and the other end open to a gas-permeable chamber for introducing medication into the patient's oral cavity and / or nasal cavity. This chamber is preferably suitable for use by the patient in a mouthpiece or sublingual form. The actuator may also include a nozzle block receiving a dispensing valve (described later), the nozzle block having an orifice channel communicating with the dispensing valve for guiding medication from the valve into the chamber.

[0055] The container is used to contain the pharmaceutical preparation of this application and has a dispensing valve operable between a non-dispensing position and a dispensing position, the dispensing valve being engageable with the nozzle block. The container can be made of aluminum, glass, stainless steel, or plastic. Furthermore, the container may have one or more coating layers inside. The container is preferably an aerosol can.

[0056] In some embodiments, the inhalation device of this application may be further configured with a counter or a dose display. The inhalation device of this application is preferably a metered-dose inhaler.

[0057] The inhalation device described in this application is a metered-dose inhaler (MDI). Upon actuation, the MDI causes a pressure change that ejects the propellant carrying the drug. The propellant vaporizes and disperses the drug, producing a sufficiently fine aerosol. Combined with the user's breathing, this aerosol effectively delivers the drug to the lungs. The physical processes involved in converting a drug solution or suspension into a fine aerosol by the MDI are complex: one is the turbulent flow and fragmentation of the jet fluid, characterized by disordered changes in pressure and velocity, resulting in unstable and transient disturbances occurring in three-dimensional space; the other is the decrease in ambient pressure, leading to flash distillation or flash evaporation, where the boiling point drops below the ambient temperature. Regardless of the mechanism, the aerosol particles produced by the MDI need to reach the target site, the lungs, through respiration. The particle size distribution affects the drug distribution in the lungs, which in turn affects the therapeutic effect. Those skilled in the art will understand that the particle size of aerosol particles can be described by the mass median aerodynamic diameter (MMAD), and the deposition momentum distribution of this particle can be measured to determine the deposition location of the particles in the lung region.

[0058] Furthermore, for such formulations to reach deep into the lungs through inhalation, the active ingredient must be in very fine particulate form, for example, with a median mass aerodynamic diameter (MMAD) of less than 10 μm. Particles with an MMAD greater than 10 μm may impinge on the throat wall and typically do not reach the lungs. Particles with an MMAD in the range of 2 μm to 5 μm usually 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.

[0059] In some embodiments, the pharmaceutical preparations, devices, methods, systems, or combinations thereof provided in this application are for local administration of medications to treat respiratory diseases. In some embodiments, the suspension or solution formed by the active pharmaceutical ingredient and propellant of this application controls the MMAD (microscopic anatomy and endothelial growth factor) of the drug aerosol particles within a range suitable for pulmonary treatment by means of appropriate pressure and propellant. The MMAD range is preferably controlled within the range of about 0.5 μm to 5 μm, more preferably within the range of about 1 μm to 4.5 μm, more preferably within the range of about 1.2 μm to 4.2 μm, and even more preferably within the range of about 1.5 μm to 4.15 μm.

[0060] In some embodiments, when this application is used to treat lung diseases, the active pharmaceutical ingredient may or may not be in a micronized or particulate form. In some preferred embodiments, the active pharmaceutical ingredient is in a micronized or particulate form. For example, it may be a micronized or particulate form with a particle size D90 (90% cumulative particle distribution) of less than about 10 micrometers (nm), preferably with a particle size D90 of less than about 5.5 micrometers, and more preferably with a particle size D90 in the range of about 4.0 to 5.3 micrometers.

[0061] The pharmaceutical formulations, devices, methods, systems, or combinations thereof provided in this application contain at least two active pharmaceutical ingredients. Those skilled in the art understand that, compared to formulations containing only a single pharmaceutical ingredient, when a single formulation contains two or more active pharmaceutical ingredients, the addition of different types of active pharmaceutical ingredients and the selection of different propellants can lead to unpredictable changes in the particle size distribution characteristics, stability, uniformity of each delivered dose, and the proportion of each delivered dose. Formulating pharmaceutical compositions with two or more active pharmaceutical ingredients is more challenging than formulating a single-ingredient formulation. In addition to considering the interactions between two or more drugs, it is also a significant challenge to consider and adjust the uniformity, proportion, and absorption site distribution of the two or more drugs in terms of delivery dose. This application provides a formulation, method, system, device, or combination thereof that can simultaneously deliver two or more drugs, and the therapeutically effective dose can be selected to be relatively lower than the therapeutically effective dose required for any single drug delivery, thereby further avoiding or reducing potential medical side effects, while simultaneously achieving a faster onset of action or a longer duration of action.

[0062] The pharmaceutical preparations, devices, methods, systems, or combinations thereof provided in this application may contain two or more active pharmaceutical ingredients selected from corticosteroids, long-acting beta-2 adrenergic agonists (LABA), short-acting beta-2 adrenergic agonists (SABA), long-acting anticholinergics (LAMA), short-acting anticholinergics (SAMA), anti-allergic drugs, anti-inflammatory drugs, bronchodilators, bronchoconstrictors, pulmonary lung surfactants, antibiotics, leukotriene inhibitors or antagonists, and mast cell inhibitors. Inhibitors or antihistamines, etc. The preferred active pharmaceutical ingredient used in this application is a corticosteroid, a long-acting beta-2 adrenergic agonist (LABA), a short-acting beta-2 adrenergic agonist (SABA), a long-acting anticholinergic (LAMA), or a short-acting anticholinergic (SAMA).

[0063] In some embodiments, this application provides an apparatus, method, system, or combination thereof suitable for treating lung diseases, comprising an actuator and an aerosol can filled with an aerosol formulation, which may be a suspension or a solution. In some preferred embodiments, the aerosol formulation is a suspension. In some embodiments, the aerosol formulation contains two pharmaceutically active ingredients selected from corticosteroids, long-acting beta-2 adrenergic agonists (LABA), short-acting beta-2 adrenergic agonists (SABA), long-acting anticholinergics (LAMA), and short-acting anticholinergics (SAMA). Preferably, the two pharmaceutically active ingredients are a combination of a corticosteroid and a beta-2 adrenergic agonist (SABA). More preferably, the two active pharmaceutical ingredients are a combination of a corticosteroid and a short-acting beta-2 adrenergic agonist (SABA). In some embodiments, the two active ingredients in the aerosol formulation may be simultaneously or separately in suspension or solution form. In some embodiments, one active pharmaceutical ingredient is a suspension and the other is a solution.

[0064] The active pharmaceutical ingredient in this application may be selected from beclomethasone, budesonide, ciclesonide, flunisolone, fluticasone, methylprednisolone, mometasone, prednisone, triamcinolone, bitolterol, carbuterol, fenoterol, hexoprenaline, isoproterenol, levosasalbutamol, orciprenaline, procaterol, ributerol, salbutamol, or procaterol.albuterol, terbutaline, tulobuterol, reproterol, ipratropium, epinephrine, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, glycopyrrolate, dexipirronium, scopolamine, tropicamide, pirenzepine (e.g., nzepine), dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, isipratropium, atropine, bezatropin, oxitropium, tripedane, cortisone, prednisone, prednisolone, dexamethasone, betamethasone, triamcinolone, or their configurational isomers, esters, salts, solvates, or combinations thereof.) In some preferred embodiments, the active pharmaceutical ingredient is selected from beclomethasone, budesonide, ciclesonide, fluticasone, mometasone, carbuterol, fenoterol, levosalbutamol, procaterol, salbutamol, or...albuterol, tulobuterol, ipratropium, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, glycopyrrolate, tiotropium, aclidinium, or their configurational isomers, esters, salts, solvates, or combinations thereof. In some embodiments, the active pharmaceutical ingredient is preferably budesonide, salbutamol or albuterol, and anticholinergic drugs, or their conformational isomers, esters, salts, or solvates, or combinations thereof. In some more preferred embodiments, the active pharmaceutical ingredient is a combination of budesonide or its conformational isomers (e.g., the 22R-conformity of budesonide), esters, salts, or solvates, with salbutamol or albuterol, or their conformational isomers, esters, salts, or solvates. Even more preferably, in some embodiments, the active pharmaceutical ingredient is a combination of budesonide and salbutamol sulfate or albuterol sulfate.

[0065] In some embodiments, the pharmaceutical preparations, devices, methods, systems, or combinations thereof provided in this application treat asthma or chronic obstructive pulmonary disease (COPD) via inhalation devices, comprising at least one pharmaceutically effective amount of a pharmaceutically active ingredient and at least one pharmaceutically acceptable propellant.

[0066] In some embodiments, the apparatus, method, system, or combination thereof provided in this application includes a container, which is an aerosol can containing a pharmaceutical preparation. The pharmaceutical preparation is a suspension or solution and contains at least two active pharmaceutical ingredients. The active pharmaceutical ingredient is a combination of budesonide or a conformational isomer (e.g., the 22R-conformation of budesonide), an ester, a salt, or a solvate, and salbutamol or albuterol or a conformational isomer, an ester, a salt, or a solvate. In some preferred embodiments, the active pharmaceutical ingredient is a combination of budesonide and salbutamol sulfate or albuterol sulfate. In some embodiments, the dose of budesonide per spray after each actuation is in the range of about 70 μg to 100 μg, preferably about 80 μg per spray. In some embodiments, the dose of salbutamol (or albuterol) per spray after each actuation is in the range of about 75 μg to 100 μg, preferably about 90 μg per spray.

[0067] In some embodiments, this application does not require the use of particulate carriers and dispersions, such as lactose, chitosan, phospholipids, and / or further modifications to the morphology of the particulate carriers and dispersions to enhance the stability of the composition, such as increasing porosity or dispersibility. In some embodiments, this application does not use particulate carriers or dispersions to promote effects such as delayed sedimentation or delayed precipitation in the drug particle suspension. Preferably, the formulation, apparatus, method, system, or combination thereof of this application achieves suspension stability without using particulate carriers or dispersions, and simultaneously promotes better drug suspension dispersion. In some embodiments, the active pharmaceutical ingredient of this application is suspended in a fluid medium (including a propellant).

[0068] In some embodiments, this application provides a formulation, method, system, or device, or a combination thereof, suitable for treating lung diseases, which allows the drug to maintain a uniform dosage during multi-dose dispensing with minimal shaking or agitation. This application maintains good drug uniformity during use. It has been found that alcohol (ethanol) and anti-agglutinating agents can be added to adjust the density of the propellant-containing solution so that the density of the propellant-containing solution is close to the drug density, achieving rapid dispersion and maintaining suspension. When drug concentrations below about 0.15% w / w (weight percentage) are used in this application, insufficient drug delivery is more likely. When drug concentrations greater than about 0.15% w / w (weight percentage) but less than about 0.25% w / w (weight percentage) are used in the formulations of this application, it is sometimes found that the drug is more likely to meet the set dosage and is stable in the formulation, thus potentially leading to increased suspension time. As drug concentration increases, for example, exceeding about 0.5% w / w (weight percentage), the drug tends to aggregate, which also increases and accelerates sedimentation. The volume occupied by the drug also increases, resulting in a rapid sedimentation effect that is detrimental to the uniformity of drug use. The drug concentration in the formulation of this application is preferably less than about 0.3% w / w (weight percentage), more preferably less than about 0.25% w / w (weight percentage), and more preferably about 0.2% w / w (weight percentage).

[0069] In some embodiments, the pharmaceutical preparations, devices, methods, systems, or combinations thereof of this application can be used to treat inflammatory or obstructive lung diseases. This lung disease or condition can 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), chronic obstructive respiratory disease (CORD), worsening of airway hyperreactivity due to drug treatment, and allergic rhinitis. Rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, emphysema, cystic fibrosis, etc.

[0070] The terms “pharmaceutical active ingredient,” “drug,” and “pharmaceutical,” as used herein, are used broadly in the sense understood by one of ordinary skill in the art, referring to any material or substance that has, or is at least believed to have, curative or therapeutic properties, and can be used to relieve disease, heal injury or other ailment, and / or pain or other symptoms, and / or for diagnostic purposes. These terms include, for example, small molecule drugs and large molecule bioactive ingredients. In this application, these terms are also used to refer to combinations that are medically effective or at least believed to be effective.

[0071] As used in this article, "therapeutic effective amount" and "pharmaceutical effective amount" refer to the amount of a compound that achieves a therapeutic effect by preventively inhibiting or preventing the onset of a disease or condition. A therapeutic effective amount can be an amount that alleviates one or more symptoms of a patient's disease or condition to a certain extent, partially or completely restores one or more physiological or biochemical parameters that are associated with or cause the disease or condition to normal, and / or reduces the likelihood of the onset of the disease or condition.

[0072] The term “about” or “approximately” as used in this article means that for a given numerical value, such as a given proportion of active pharmaceutical ingredients, numerical value, particle size, particle diameter, particle size distribution characteristics, uniformity of delivery dose, etc., the indicated value contains a deviation within ±10%.

[0073] As used herein, the term "emitted dose" or "ED (Emitted Dose)" refers to the mass of the active pharmaceutical ingredient emitted from the device. Those skilled in the art will understand that the emitted dose ED is obtained and validated from a Dosage Unit Sampling Apparatus (DUSA).

[0074] As used herein, the term "fine particle dose" or "FPD" refers to the total mass of drug particles smaller than a certain aerodynamic diameter after the drug is emitted from the device. Unless otherwise specified, this aerodynamic diameter is generally considered to be 5 μm by those skilled in the art. In other words, unless a specific MMAD is specified, the FPD refers to the FPD value occupied by drug particles with an MMAD of less than 5 μm.

[0075] The term "fine particulate fraction" or "FPF" as used in this article refers to the proportion of a specific total MMAD value delivered relative to the total dose emitted, calculated by dividing FPD by ED.

[0076] The term “MMAD” as used herein refers to the median mass aerodynamic diameter, which is the aerodynamic diameter of aerosol particles. The calculation of MMAD is based on the United States Pharmacopoeia (USP), and the relevant content of the USP is incorporated into this application.

[0077] The term "propellant" as used in this article refers to a pharmacologically inert substance that produces a sufficiently high vapor pressure at normal room temperature to propel the drug from the canister into the patient's mouth during MDI actuation, allowing it to enter the lungs through the respiratory tract via the patient's breathing.

[0078] The term "inhalable" as used in this article generally refers to particles, aggregates, droplets, etc., that are small enough to be inhaled and reach the airways of the lungs.

[0079] As used herein, the term "suspension" refers to a substance that provides a continuous phase in which the active pharmaceutical ingredient particles can be dispersed to provide a co-suspension formulation. For example, the active pharmaceutical ingredient in this application is in particulate form in the solute and is essentially an aerosol formulation that is insoluble in the propellant.

[0080] As used in this article, "suspension stability" and "stable suspension" refer to suspension formulations that maintain the properties of active agent particles over a period of time. Suspension stability can be measured by the uniformity of delivered dosage.

[0081] The term “labeled dose (LD)” as used in this article refers to the mass of medication that can be delivered each time the inhalation device is activated, or the dose indicated on the inhaler packaging.

[0082] The term “geometric standard deviation (GSD)” used in this article refers to the dispersion of the measured particle size; it is defined as the ratio of the median particle size to the median particle size ± 1 standard deviation (σ). An aerosol with a GSD of 1.22 is considered a polydisperse aerosol, and most therapeutic aerosols are polydisperse aerosols with a GSD between 2 and 3.

[0083] Example

[0084] The raw materials, chromatography conditions, drug delivery (DDU) test, and aerodynamic particle size distribution test used in the following examples are described below.

[0085] raw material

[0086] Micronized salbutamol sulfate was purchased from Cambrex (Paullo, Milan, Italy), with a 90% volume particle size of NMT 4.5 μm. Micronized budesonide was purchased from Chemo (Saronno, Varese, Italy), with a 90% volume particle size ranging from 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 / 50PRE7 metering valves were purchased from Aptar (UK). 14ml fluorocarbon polymerization (FCP) coated aluminum cans were purchased from H&T Presspart (UK). Regarding the commercially available single-component formulations used as reference standards, the salbutamol sulfate reference standard was the commercially available MDI from Teva Pharmaceutical Industries Co., Ltd. The budesonide reference standard is a commercially available MDI product.

[0087] Chromatographic conditions

[0088] The high-performance liquid chromatography (HPLC) system consisted of an Agilent 1260 Infinity II chromatography system equipped with a VWD detector (both purchased from Agilent Technologies, California, USA). A HIQ sil C18 HS 5μm 4.6mm × 250mm column (Oligaga Ltd., Taiwan) was used. The UV detection bar wavelength was 220nm, changing to 240nm after 8 minutes. The retention time for salbutamol sulfate was 4.6 minutes, and for budesonide, it was 17.9 minutes and 18.5 minutes, respectively.

[0089] Drug delivery (DDU) trials

[0090] For drug delivery testing, instrument A was used at a flow rate of 28.3 L / min (±5%), following the United States Pharmacopeia monograph (USP 601). Each sample underwent a three-stage purging process before sampling. After purging, two purging cycles were collected in a DUSA tube. Subsequently, the purging device and DUSA tube were rinsed with an appropriate amount of diluent. The rinse mixture was analyzed by HPLC.

[0091] Aerodynamic Particle Size Distribution (APSD) Test

[0092] APSD detection was performed using a next-generation impact sampler (NGI). This device is a tiered impact sampler with 7 stages and a micropore collector (MOC). Following the United States Pharmacopeia monograph (USP 601), the instrument was used at a flow rate of 30 L / min (±5%). Each cup of the impact sampler was coated with hexane (w / v) containing 1% silicone oil. After four starts, the cups were rinsed with an appropriate amount of diluent, and the rinse mixture was analyzed by HPLC.

[0093] Example 1: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, and 1% anhydrous ethanol.

[0094] The preparation steps for the metered-dose inhaler are as follows: First, weigh the required amounts of the two active drug particles and 1% w / w (weight percentage) anhydrous ethanol and place them in the FCP aluminum canister, then seal and compact the canister using the metering valve. Next, pour the required amount of HFO-1234ze(E) into the sealed FCP aluminum canister through the metering valve, followed by 10 minutes of ultrasonic agitation to form the drug mixture. As shown in Table 1, the drug particles in this mixture are suspended in HFO-1234ze(E).

[0095] Table 1. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 1% w / w anhydrous ethanol and HFO-1234ze(E) propellant.

[0096] Example 2: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, and 5% w / w (weight percentage) anhydrous ethanol.

[0097] The preparation steps for the metered-dose inhaler are as follows: First, weigh the required amount of the two active drug particles and mix them with 5% w / w (weight percentage) anhydrous ethanol to form a mixture. Add this mixture to the FCP aluminum canister and then seal and crimp it using the metering valve. Next, pour the required amount of HFO-1234ze(E) into the sealed and crimped FCP aluminum canister through the metering valve, and then perform ultrasonic agitation for 10 minutes to form the drug mixture. As shown in Table 2, salbutamol sulfate is suspended in HFO-1234ze(E), and budesonide is completely dissolved in solution.

[0098] Table 2. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 5% w / w anhydrous ethanol and HFO-1234ze(E) propellant.

[0099] Example 3: A metered-dose inhaler containing salbutamol sulfate and budesonide active particles and 10% w / w (weight percentage) anhydrous ethanol.

[0100] The preparation steps for the metered-dose inhaler are the same as in Example 2. As shown in Table 3, salbutamol sulfate is suspended in HFO-1234ze(E), and budesonide is completely dissolved in solution.

[0101] Table 3. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 10% w / w anhydrous ethanol and HFO-1234ze(E) propellant.

[0102] Example 4: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, and 20% w / w (weight percentage) anhydrous ethanol.

[0103] The preparation steps for the metered-dose inhaler are the same as in Example 2. As shown in Table 4, salbutamol sulfate is suspended in HFO-1234ze(E), and budesonide is completely dissolved in solution.

[0104] Table 4. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 20% ​​w / w anhydrous ethanol and HFO-1234ze(E) propellant.

[0105] Example 5: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, and 0.5% w / w (weight percentage) PEG-400.

[0106] The preparation steps for the metered-dose inhaler are as follows: First, weigh the required amounts of the two active drug particles and 0.5% w / w (weight percentage) anticoagulant and place them in the FCP aluminum canister, then seal and crimp the canister using the metering valve. Next, pour the required amount of HFO-1234ze(E) into the sealed and crimped FCP aluminum canister through the metering valve, followed by 10 minutes of ultrasonic agitation to form the drug mixture. As shown in Table 5, the drug particles in this mixture are suspended in HFO-1234ze(E).

[0107] Table 5. Pressurized inhalation suspension of salbutamol sulfate and budesonide, containing 0.5% w / w PEG-400 and HFO-1234ze(E) propellant.

[0108] Example 6: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, and 0.1% w / w (weight percentage) PEG-1000.

[0109] The preparation steps for the metered-dose inhaler are as shown in Example 5. As shown in Table 6, the drug particles in the mixture are suspended in HFO-1234ze(E).

[0110] Table 6. Pressurized inhalation suspension of salbutamol sulfate and budesonide, containing 0.1% w / w PEG-1000 and HFO-1234ze(E) propellant.

[0111] Example 7: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, and 0.5% w / w (weight percentage) PEG-1000.

[0112] The preparation steps for the metered-dose inhaler are as shown in Example 5. As shown in Table 7, the drug particles in the mixture are suspended in HFO-1234ze(E).

[0113] Table 7. Pressurized inhalation suspension of salbutamol sulfate and budesonide, containing 0.5% w / w PEG-1000 and HFO-1234ze(E) propellant.

[0114] Example 8: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, along with 1% w / w (weight percentage) anhydrous ethanol and 0.1% w / w (weight percentage) PEG-400.

[0115] The preparation steps for the metered-dose inhaler are as follows: First, weigh the required amounts of the two active drug particles, and place them in the FCP aluminum canister along with 1% w / w (weight percentage) anhydrous ethanol and 0.1% w / w (weight percentage) anticoagulant. Then, seal and crimp the canister using the metering valve. Next, pour the required amount of HFO-1234ze(E) into the sealed and crimped FCP aluminum canister through the metering valve, and then perform ultrasonic agitation for 10 minutes to form the drug mixture. As shown in Table 8, the drug particles in this mixture are suspended in HFO-1234ze(E).

[0116] Table 8. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 1% w / w anhydrous ethanol and 0.1% w / w PEG-400, as well as HFO-1234ze(E) propellant.

[0117] Example 9: A metered-dose inhaler containing salbutamol sulfate and budesonide active particles, 1% w / w (weight percentage) anhydrous ethanol, and 0.1% w / w (weight percentage) PEG-1000.

[0118] The preparation steps for the metered-dose inhaler are as shown in Example 8. As shown in Table 9, the drug particles in the mixture are suspended in HFO-1234ze(E).

[0119] Table 9. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 1% w / w anhydrous ethanol and 0.1% w / w PEG-1000, as well as HFO-1234ze(E) propellant.

[0120] Example 10: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, along with 10% w / w (weight percentage) anhydrous ethanol and 0.1% w / w (weight percentage) PEG-400.

[0121] Preparation steps for a metered-dose inhaler: First, weigh the required amounts of the two active drug particles and mix them with 10% w / w (weight percentage) anhydrous ethanol and 0.1% w / w (weight percentage) anticoagulant to form a mixture. Add the mixture to the FCP aluminum canister and then seal and crimp it using the metering valve. Next, pour the required amount of HFO-1234ze(E) into the sealed and crimped FCP aluminum canister through the metering valve, and then perform ultrasonic agitation for 10 minutes to form the drug mixture. As shown in Table 10, salbutamol sulfate is suspended in HFO-1234ze(E), and budesonide is completely dissolved in solution.

[0122] Table 10. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 10% w / w anhydrous ethanol and 0.1% w / w PEG-400, as well as HFO-1234ze(E) propellant.

[0123] Example 11: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, along with 10% w / w (weight percentage) anhydrous ethanol and 0.1% w / w (weight percentage) PEG-1000.

[0124] The preparation steps for the metered-dose inhaler are the same as in Example 10. As shown in Table 11, salbutamol sulfate is suspended in HFO-1234ze(E), and budesonide is completely dissolved in solution.

[0125] Table 11. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 10% w / w anhydrous ethanol and 0.1% w / w PEG-1000, as well as HFO-1234ze(E) propellant.

[0126] Example 12: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, along with 2% w / w (weight percentage) anhydrous ethanol and 0.3% w / w (weight percentage) PEG-1000.

[0127] The preparation steps for the metered-dose inhaler are the same as in Example 8. As shown in Table 12, the drug particles in this mixture are suspended in HFO-1234ze(E).

[0128] Table 12. Pressurized inhalation suspension of salbutamol sulfate and budesonide, containing 2% w / w anhydrous ethanol and 0.3% w / w PEG-1000, and HFO-1234ze(E) propellant.

[0129] Example 13: A metered-dose inhaler containing two active particles, salbutamol sulfate and budesonide, along with 10% w / w (weight percentage) anhydrous ethanol and 0.5% w / w (weight percentage) PEG-1000.

[0130] The preparation steps for the metered-dose inhaler are the same as in Example 10. As shown in Table 13, salbutamol sulfate is suspended in HFO-1234ze(E), and budesonide is completely dissolved in solution.

[0131] Table 13. Pressurized inhalation suspensions of salbutamol sulfate and budesonide, containing 10% w / w anhydrous ethanol and 0.5% w / w PEG-1000, as well as HFO-1234ze(E) propellant.

[0132] This study compared the drug delivery effects of pressurized inhaled suspensions of salbutamol sulfate and budesonide using different formulations with HFO-1234ze propellant. The drug delivery amounts of different embodiments are shown in Figures 1 to 3 and Table 14, expressed as a percentage of the actual delivered dose relative to the labeled delivered dose (108 mcg for salbutamol sulfate and 80 mcg for budesonide). (Based on the United States Pharmacopeia) <601> The total amount of drug collected from all DUSA devices (residual amount) divided by the total number of starts for each emission measurement should generally be within the range of not less than 85% and not more than 115% of the labeled delivery dose to meet the standard. Therefore, the pharmacopoeia stipulates that the drug delivery dose should not be less than 85% of the labeled dose. The compiled test results show that the commercially available control products all met this standard; however, in the formulations of Example 1 (1% w / w (weight percentage) anhydrous ethanol) and Examples 5 and 7 (0.5% w / w (weight percentage) PEG), the drug delivery amount was lower than the standard requirement. Furthermore, the tests revealed that drug delivery was impossible in the 0.1% w / w (weight percentage) PEG-400 formulation due to severe aggregation effects. Further, even increasing the dosage to 0.5% w / w (weight percentage) did not improve delivery; and for PEG 1000, increasing the dosage to 0.5% w / w (weight percentage) actually decreased drug delivery compared to 0.1% w / w (weight percentage). Therefore, the experimental data shows that in formulations using ethanol or PEG alone, the drug delivery efficiency varies with different concentrations of ethanol or PEG and different types of PEG. In contrast, when formulations use both ethanol and PEG, the drug delivery rate remains above 85% at various concentration combinations, indicating that the drug delivery effect is better when both are used simultaneously.

[0133] Table 15 summarizes the aerodynamic particle size distribution (APSD) of salbutamol sulfate and budesonide, comparing them with commercially available products and examples from this application, including fine particle dose (FPD), fine particle fraction (FPF), median mass aerodynamic diameter (MMAD), and laryngeal sedimentation rate. Surprisingly, while the formulation using anhydrous ethanol alone showed good drug delivery (DDU) data, budesonide and salbutamol sulfate exhibited drastically different APSD performance. The summarized data shows that while increasing the amount of anhydrous ethanol used improved the FPD and FPF of budesonide compared to commercially available single-component formulations, and decreased the sedimentation rate in the throat, the effect on salbutamol sulfate was worse than that of commercially available single-component formulations with increasing ethanol usage. Drug delivery (DDU) performance was generally poor when PEG was used alone; however, significant optimization occurred when it was used in combination with anhydrous ethanol. Regardless of whether the concentration of anhydrous ethanol is high or low, or the molecular weight of PEG is different, superior results compared to commercially available single-component formulations are observed in fine particles and in terms of laryngeal deposition. When both ethanol and PEG are used in the formulation, FPD, FPF, and MMAD values ​​are equal to or better than the evaluation standards at various combinations of their concentrations, and both drugs also have lower laryngeal deposition rates.

[0134] Table 15

[0135] On the other hand, regarding the pressurized inhalation suspensions of salbutamol sulfate and budesonide using different formulations of HFO-1234ze as propellants, the results show that for the 0.5% w / w PEG1000 formulation, although the FPD and FPF data are comparable to the control commercially available product, the DDU is on the verge of meeting the standard. In Example 13, when the amount of PEG used was increased to approximately 0.5% w / w, although the FPD and FPF of budesonide were still improved compared to the commercially available single-component formulation, the FPF of salbutamol sulfate was significantly lower than that of the commercially available product.

[0136] This application provides inhaled pharmaceutical formulations and uses a metered-dose inhaler (MDI) for treating asthma and other chronic obstructive pulmonary diseases and for delivering the medication to the treatment site. Therefore, this application includes formulations for treating lung diseases in organisms (e.g., humans or animals), including administering the composition of this application containing a compound pharmaceutical product and an inhalation device to the organism in need of treatment. Although this application has been described and illustrated above with reference to certain preferred embodiments, this application is not necessarily limited to these examples and embodiments.

Claims

1. An inhaled pharmaceutical preparation comprising: Propellant; At least two active pharmaceutical ingredients; Co-solvent, selected from ethanol or anhydrous ethanol; and Anti-coagulant; The propellant mentioned therein is tetrafluoropropylene.

2. The inhaled pharmaceutical preparation of claim 1, wherein the co-solvent is anhydrous ethanol and the anticoagulant is polyethylene glycol (PEG).

3. The inhaled pharmaceutical preparation of claim 1, wherein the active pharmaceutical ingredient is selected from any combination of two of the following: corticosteroids, beta-2 adrenergic agonists, and anticholinergics.

4. The inhaled pharmaceutical preparation of claim 1, wherein the concentrations of the at least two active pharmaceutical ingredients are both less than about 0.3% (w / w).

5. The inhaled pharmaceutical formulation of claim 4, wherein the cosolvent content in the formulation is less than about 12% (w / w); and the anticoagulant content in the formulation is less than 0.5% (w / w).

6. The inhaled pharmaceutical formulation of claim 5, wherein the cosolvent is present in a concentration of less than about 10% (w / w) in the formulation; and the anticoagulant is present in a concentration of about 0.1% (w / w) to about 0.45% (w / w) in the formulation.

7. The inhaled pharmaceutical preparation of claim 1, wherein the active pharmaceutical ingredient is selected from corticosteroids and short-acting beta-glycemic agents; wherein The corticosteroid drug is budesonide; and The short-acting ethylenediamine synergist is salbutamol sulfate.

8. The inhaled pharmaceutical formulation of claim 3, wherein the corticosteroid is budesonide, and the content of the corticosteroid in the formulation is 0.136% to 0.147%; and the short-acting beta-glycemic synergist is salbutamol sulfate, and the content of the salbutamol in the formulation is 0.185% to 0.200%.

9. An inhalation device comprising: Actuator; and An aerosol can for filling an inhaled pharmaceutical preparation as described in any one of claims 1 to 8; The actuator includes a housing and a nozzle block for a metering valve; One end of the housing is open to accommodate the aerosol can, and the other end is open to form an airflow-through chamber for introducing the inhaled pharmaceutical preparation into the patient's oral cavity and / or nasal cavity. The nozzle block has an orifice channel that communicates with the dispensing valve and is used to guide the inhaled pharmaceutical preparation from the dispensing valve into the chamber.

10. Use of the inhaled pharmaceutical preparation according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of lung diseases.

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